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path(MESH:"Alzheimer Disease")

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Entity

Name
Alzheimer Disease
Namespace
mesh
Namespace Version
20180828
Namespace URL
https://raw.githubusercontent.com/pharmacome/terminology/1b20f0637c395f8aa89c2e2e342d7b704062c242/external/mesh-names.belns

Appears in Networks 77

Functional aspects of meningeal lymphatics in ageing and Alzheimer’s disease v1.0.0

Identification of a novel aspartic protease (Asp 2) as beta-secretase v1.0.0

Estrogen receptor-α is localized to neurofibrillary tangles in Alzheimer's disease v1.0.0

Amyloid β oligomers (AβOs) in Alzheimer’s disease v1.0.0

Amyloid Precursor Protein Trafficking, Processing, and Function v1.0.0

Amyloid Precursor Protein Trafficking, Processing, and Function by Thinakaran, et al., 2008

APP processing in Alzheimer's disease v1.0.1

APP processing in Alzheimer's disease

Proteolytic processing of Alzeimer's beta-amyloid precursor protein v1.0.1

albuquerque2009 v1.0.0

This file encodes the article Mammalian Nicotinic Acetylcholine Receptors: From Structure to Function by Albuquerque et al, 2009

Nicotinic acetylcholine receptor signalling: roles in Alzheimer's disease and amyloid neuroprotection. v1.0.0

Activation of M1 and M4 muscarinic receptors as potential treatments for Alzheimer's disease and schizophrenia. v1.0.0

This file encodes the article Activation of M1 and M4 muscarinic receptors as potential treatments for Alzheimer’s disease and schizophrenia by Choi et al, 2014

Nicotinic Acetylcholine Receptors and Nicotinic Cholinergic Mechanisms of the Central Nervous System v1.0.0

Alzheimer's Disease: Targeting the Cholinergic System v1.0.0

M1 muscarinic acetylcholine receptor in Alzheimer’s disease v1.0.0

This file encodes the article M1 muscarinic acetylcholine receptor in Alzheimer’s disease by Jiang et al, 2014

Role of the nicotinic acetylcholine receptor in Alzheimer's disease pathology and treatment v1.0.1

A role for b2* nicotinic receptors in a model of local amyloid pathology induced in dentate gyrus v1.0.0

Nuclear receptors as therapeutic targets for Alzheimer's disease. v1.0.0

Nicotinic Receptor Abnormalities of Alzheimer’s Disease: Therapeutic Implications v1.0.0

Selective activation of α7 nicotinic acetylcholine receptor by PHA-543613 improves Aβ25-35-mediated cognitive deficits in mice v1.0.0

Nicotinic receptors: allosteric transitions and therapeutic targets in the nervous system v1.0.0

This document contains the curation of the review article Nicotinic receptors: allosteric transitions and therapeutic targets in the nervous system by Taly et al. 2009

Chaperoning α7 neuronal nicotinic acetylcholine receptors v1.0.0

Naturally-expressed nicotinic acetylcholine receptor subtypes v1.0.0

Neuronal and Extraneuronal Nicotinic Acetylcholine Receptors. v1.0.0

Anti-inflammatory activity of anatabine via inhibition of STAT3 phosphorylation v1.0.0

A chaperome subnetwork safeguards proteostasis in aging and neurodegenerative disease. v1.0.0

The Ubiquitin Proteasome System in Neurodegenerative Diseases: Sometimes the Chicken, Sometimes the Egg v1.0.0

The Biology of Proteostasis in Aging and Disease v1.0.0

Abnormal Alzheimer-like phosphorylation of tau-protein by cyclin-dependent kinases cdk2 and cdk5 v1.0.0

Promoting the clearance of neurotoxic proteins in neurodegenerative disorders of ageing v1.0.0

Interplay of pathogenic forms of human tau with different autophagic pathways v1.0.1

Multivalent cross-linking of actin filaments and microtubules through the microtubule-associated protein Tau v1.0.0

Tau clearance mechanisms and their possible role in the pathogenesis of Alzheimer disease v1.0.0

Analysis of Isoform-specific Tau Aggregates Suggests a Common Toxic Mechanism Involving Similar Pathological Conformations and Axonal Transport Inhibition v1.0.1

Alzheimer's disease-type neuronal tau hyperphosphorylation induced by A beta oligomers v1.0.0

This document contains the bel code for the Article Alzheimer’s disease-type neuronal tau hyperphosphorylation induced by Abeta oligomers by De Felice et al

Pathogenic forms of tau inhibit kinesin-dependent axonal transport through a mechanism involving activation of axonal phosphotransferases. v1.0.0

Tau degradation: the ubiquitin-proteasome system versus the autophagy-lysosome system. v1.0.0

Molecular chaperones and regulation of tau quality control: strategies for drug discovery in tauopathies v1.0.0

Tau protein aggregation is associated with cellular senescence in the brain v1.0.0

Neuropathogenic role of adenylate kinase-1 in Aβ-mediated tau phosphorylation via AMPK and GSK3β. v1.0.0

Tau oligomers-Cytotoxicity, propagation, and mitochondrial damage v1.0.0

Tau oligomers-Cytotoxicity, propagation, and mitochondrial damage from Shafiei et al., 2017

Imbalances in the Hsp90 Chaperone Machinery: Implications for Tauopathies v1.0.0

Tau Protein Hyperphosphorylation and Aggregation in Alzheimer’s Disease and Other Tauopathies, and Possible Neuroprotective Strategies v1.0.0

Neuronal uptake and propagation of a rare phosphorylated high-molecular-weight tau derived from Alzheimer’s disease brain v1.0.1

Clearance systems in the brain-implications for Alzheimer disease. v1.0.1

Pseudophosphorylation of tau at S422 enhances SDS-stable dimer formation and impairs both anterograde and retrograde fast axonal transport. v1.0.0

Tau oligomers and tau toxicity in neurodegenerative disease v1.0.0

Tau oligomers and tau toxicity in neurodegenerative disease by Ward et al., 2012

Clearance of Amyloid Beta and Tau in Alzheimer’s Disease:from Mechanisms to Therapy v1.0.1

Extracellular Tau and Its Potential Role in the Propagation of Tau Pathology v1.0.0

Tau Biochemistry v1.2.5

Tau Biochemistry Section of NESTOR

Tau Modifications v1.9.5

Tau Modifications Sections of NESTOR

The role of inflammasome in Alzheimer’s disease v1.0.3

Inflammasome Involvement in Alzheimer’s Disease v1.0.0

Amyloid-Binding Alcohol Dehydrogenase (ABAD) Inhibitors for the Treatment of Alzheimer’s Disease v1.0.0

Oxidative stress in health and disease: The therapeutic potential of Nrf2 activation v1.0.0

Phosphatase: PP2A structural importance, regulation and its aberrant expression in cancer v1.0.0

Protein phosphatase 2A dysfunction in Alzheimer’s disease v1.0.0

Axonal Transport, Tau Protein, and Neurodegeneration in Alzheimer’s Disease v1.0.0

PP2A and Alzheimer Disease v1.0.0

Model systems of protein-misfolding diseases reveal chaperone modifiers of proteotoxicity v1.0.0

Alzheimer’s disease and the autophagic-lysosomal system v1.0.0

The Ubiquitin–Proteasome System and the Autophagic–Lysosomal System in Alzheimer Disease v1.0.0

Autophagy and the ubiquitin-proteasome system: collaborators in neuroprotection v1.0.0

Pathological missorting of endogenous MAPT/Tau in neurons caused by failure of protein degradation systems v1.0.0

Tau Trimers Are the Minimal Propagation Unit Spontaneously Internalized to Seed Intracellular Aggregation v1.0.0

Inert and seed-competent tau monomers suggest structural origins of aggregation v1.0.0

Caenorhabditis elegans models of tauopathy v1.0.0

Carboxy terminus heat shock protein 70 interacting protein reduces tau-associated degenerative changes v1.0.0

Alzheimer's disease pathological lesions activate the spleen tyrosine kinase. v1.0.0

Tau in physiology and pathology v1.0.0

New insights into the role of microRNAs and long noncoding RNAs in most common neurodegenerative diseases v1.0.0

Increased NF-κB signalling up-regulates BACE1 expression and its therapeutic potential in Alzheimer's disease. v1.0.0

Nuclear Factor Kappa-light-chain-enhancer of Activated B Cells (NF-κB) - a Friend, a Foe, or a Bystander - in the Neurodegenerative Cascade and Pathogenesis of Alzheimer's Disease v1.0.0

Phytochemicals as inhibitors of NF-κB for treatment of Alzheimer’s disease v1.0.0

Upstream regulators and downstream effectors of NF-κBinAlzheimer's disease v1.0.0

Significance of NF-κB as a pivotal therapeutic target in the neurodegenerative pathologies of Alzheimer's disease and multiple sclerosis v1.0.0

mTOR-Related Brain Dysfunctions in Neuropsychiatric Disorders v1.0.0

Activity-dependent neuroprotective protein deficiency models synaptic and developmental phenotypes of autism-like syndrome v1.0.0

Pathological missorting of endogenous MAPT/Tau in neurons caused by failure of protein degradation systems v1.0.1

In-Edges 536

a(CHEBI:"amyloid-beta") positiveCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

Staining for amyloid-β in the brains of nine patients with Alzheimer’s disease and eight controls without Alzheimer’s disease (Extended Data Table 1) revealed, as expected, marked parenchymal deposition of amyloid-β in the brains of patients with Alzheimer’s disease, but not in the brains of the controls without Alzheimer’s disease (Extended Data Fig. 9l, m) PubMed:30046111

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Confidence
Medium
MeSH
Brain
MeSH
Parenchymal Tissue

a(CHEBI:"amyloid-beta") positiveCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

Notably, when compared to tissue from controls, all samples from patients with Alzheimer’s disease demonstrated striking vascular amyloid-β pathology in the cortical leptomeninges (Extended Data Fig. 9l, m) and amyloid-β deposition in the dura mater adjacent to the superior sagittal sinus (Fig. 3i, j) or further away from the sinus (Fig. 3k, l) PubMed:30046111

Appears in Networks:
Annotations
Confidence
Medium
MeSH
Dura Mater
MeSH
Superior Sagittal Sinus

a(CHEBI:"amyloid-beta") positiveCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

These findings showed that prominent meningeal amyloid-β deposition observed in patients with Alzheimer’s disease is also observed in mouse models of Alzheimer’s disease after meningeal lymphatic vessel ablation PubMed:30046111

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Annotations
Confidence
Medium
MeSH
Meninges
MeSH
Alzheimer Disease

a(HBP:HBP00018) positiveCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

Extracellular deposition of amyloid-β aggregates, the main constituent of senile plaques, is considered to be a pathological hallmark of Alzheimer’s disease that contributes to neuronal dysfunction and behavioural changes PubMed:30046111

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Confidence
Medium
MeSH
Extracellular Space

act(a(MESH:"Lymphatic Vessels")) association path(MESH:"Alzheimer Disease") View Subject | View Object

Notably, although the fold change in significantly altered genes after lymphatic ablation and MWM was moderate (−1.79 < log2(fold change) < 1.69), functional enrichment analysis (Extended Data Fig. 5o, p) revealed changes in gene sets associated with neurodegenerative diseases, such as Huntington’s, Parkinson’s and Alzheimer’s disease (Extended Data Fig. 5o) PubMed:30046111

Appears in Networks:
Annotations
Confidence
High
MeSH
Meninges

a(CHEBI:"amyloid-beta polypeptide 42") negativeCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

Despite enhanced Aβ42 accumulation in AD brain (Lewczuk et al. 2003), concentrations of monomeric Aβ42 in the CSF of AD patients are decreased PubMed:29196815

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Annotations
MeSH
Extracellular Space
Cell Ontology (CL)
neuron
Confidence
High
MeSH
Hippocampus

a(CHEBI:"amyloid-beta") positiveCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

The histopathological changes in the brain include the presence of extracellular amyloid plaques consisted of various peptide variants of amyloid β (Aβ) and accumulation of intracellular neurofibrillary tangles (NFTs) composed mainly of phosphorylated Tau proteins (pTau), localized predominantly in neurons (reviewed by Serrano-Pozo et al. 2011). PubMed:29196815

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Confidence
Medium

a(CHEBI:"amyloid-beta") positiveCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

Amyloid hypothesis is supported by the fact that progressive Aβ deposition is observed in early, preclinical stages of AD and, finally, in all AD patients. PubMed:29196815

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Confidence
High

a(GO:"neurofibrillary tangle") positiveCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

The histopathological changes in the brain include the presence of extracellular amyloid plaques consisted of various peptide variants of amyloid β (Aβ) and accumulation of intracellular neurofibrillary tangles (NFTs) composed mainly of phosphorylated Tau proteins (pTau), localized predominantly in neurons (reviewed by Serrano-Pozo et al. 2011). PubMed:29196815

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Annotations
Confidence
Medium

a(HBP:HBP00074) positiveCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

In very early stages of AD pathology, before the appearance of amyloid plaques, oligomers assemble perisomatically, rather than intracellularly, surrounding individual diffuse neurons. PubMed:29196815

Appears in Networks:
Annotations
MeSH
Extracellular Space
Cell Ontology (CL)
neuron
Confidence
High

a(HBP:HBP00074) positiveCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

They revealed increases in AβOs and soluble TNF-R plasma levels that accurately differentiated mild AD patients from control subjects and to some extent from amnestic mild cognitive impairment (aMCI) patients. PubMed:29196815

Appears in Networks:
Annotations
MeSH
Extracellular Space
Cell Ontology (CL)
neuron
Confidence
High
MeSH
Plasma

a(HBP:HBP00076) positiveCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

Using a novel misfolded protein assay for the detection of soluble oligomers composed of Aβx-40 and Aβx-42 peptides, Gao and co-workers demonstrated also increased levels of oligomeric Aβ40 in CSF, which may be a potential biomarker for the diagnosis of AD (Gao et al. 2010). PubMed:29196815

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Annotations
MeSH
Extracellular Space
Cell Ontology (CL)
neuron
Confidence
High
MeSH
Cerebrospinal Fluid

a(HBP:HBP00076) biomarkerFor path(MESH:"Alzheimer Disease") View Subject | View Object

These results suggest that circulating Aβ40 oligomers, and not only Aβ42 oligomers, could be a potential new biomarker in early AD. PubMed:29196815

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Annotations
MeSH
Extracellular Space
Cell Ontology (CL)
neuron
Confidence
High
MeSH
Cerebrospinal Fluid

a(MESH:"Amyloid beta-Peptides") positiveCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

The histopathological changes in the brain include the presence of extracellular amyloid plaques consisted of various peptide variants of amyloid β (Aβ) and accumulation of intracellular neurofibrillary tangles (NFTs) composed mainly of phosphorylated Tau proteins (pTau), localized predominantly in neurons (reviewed by Serrano-Pozo et al. 2011). PubMed:29196815

Appears in Networks:
Annotations
Confidence
Medium

bp(GO:aging) increases path(MESH:"Alzheimer Disease") View Subject | View Object

The risk factors of AD include: increasing age, vascular factors such as smoking, obesity, and diabetes (Reitz and Mayeux 2014) as well as genetic mutations. PubMed:29196815

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Confidence
High

g(HBP:HBP00030) increases path(MESH:"Alzheimer Disease") View Subject | View Object

However, a significant risk of AD development is related to certain genetic changes: the sporadic form of AD can be associated with the presence of apolipoprotein E (APOE) ε4 genotype (Holtzman et al. 2012; Spinney 2014), whereas the familial Alzheimer’s disease (FAD) can be linked to mutations in presenilin1 (PS1), presenilin2 (PS2), and amyloid precursor protein (APP) genes (reviewed by Hardy and Gwinn-Hardy 1998). PubMed:29196815

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Confidence
High

g(HGNC:APP, var("?")) increases path(MESH:"Alzheimer Disease") View Subject | View Object

However, a significant risk of AD development is related to certain genetic changes: the sporadic form of AD can be associated with the presence of apolipoprotein E (APOE) ε4 genotype (Holtzman et al. 2012; Spinney 2014), whereas the familial Alzheimer’s disease (FAD) can be linked to mutations in presenilin1 (PS1), presenilin2 (PS2), and amyloid precursor protein (APP) genes (reviewed by Hardy and Gwinn-Hardy 1998). PubMed:29196815

Appears in Networks:
Annotations
Confidence
High

g(HGNC:PSEN1, var("?")) increases path(MESH:"Alzheimer Disease") View Subject | View Object

However, a significant risk of AD development is related to certain genetic changes: the sporadic form of AD can be associated with the presence of apolipoprotein E (APOE) ε4 genotype (Holtzman et al. 2012; Spinney 2014), whereas the familial Alzheimer’s disease (FAD) can be linked to mutations in presenilin1 (PS1), presenilin2 (PS2), and amyloid precursor protein (APP) genes (reviewed by Hardy and Gwinn-Hardy 1998). PubMed:29196815

Appears in Networks:
Annotations
Confidence
High

g(HGNC:PSEN2, var("?")) increases path(MESH:"Alzheimer Disease") View Subject | View Object

However, a significant risk of AD development is related to certain genetic changes: the sporadic form of AD can be associated with the presence of apolipoprotein E (APOE) ε4 genotype (Holtzman et al. 2012; Spinney 2014), whereas the familial Alzheimer’s disease (FAD) can be linked to mutations in presenilin1 (PS1), presenilin2 (PS2), and amyloid precursor protein (APP) genes (reviewed by Hardy and Gwinn-Hardy 1998). PubMed:29196815

Appears in Networks:
Annotations
Confidence
High

p(HGNC:NGFR) positiveCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

They revealed increases in AβOs and soluble TNF-R plasma levels that accurately differentiated mild AD patients from control subjects and to some extent from amnestic mild cognitive impairment (aMCI) patients. PubMed:29196815

Appears in Networks:
Annotations
MeSH
Extracellular Space
Cell Ontology (CL)
neuron
Confidence
High
MeSH
Plasma

path(MESH:"Diabetes Mellitus") increases path(MESH:"Alzheimer Disease") View Subject | View Object

The risk factors of AD include: increasing age, vascular factors such as smoking, obesity, and diabetes (Reitz and Mayeux 2014) as well as genetic mutations. PubMed:29196815

Appears in Networks:
Annotations
Confidence
High

path(MESH:"Plaque, Amyloid") positiveCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

The histopathological changes in the brain include the presence of extracellular amyloid plaques consisted of various peptide variants of amyloid β (Aβ) and accumulation of intracellular neurofibrillary tangles (NFTs) composed mainly of phosphorylated Tau proteins (pTau), localized predominantly in neurons (reviewed by Serrano-Pozo et al. 2011). PubMed:29196815

Appears in Networks:
Annotations
Confidence
Medium

path(MESH:Obesity) increases path(MESH:"Alzheimer Disease") View Subject | View Object

The risk factors of AD include: increasing age, vascular factors such as smoking, obesity, and diabetes (Reitz and Mayeux 2014) as well as genetic mutations. PubMed:29196815

Appears in Networks:
Annotations
Confidence
High

path(MESH:Smoking) increases path(MESH:"Alzheimer Disease") View Subject | View Object

The risk factors of AD include: increasing age, vascular factors such as smoking, obesity, and diabetes (Reitz and Mayeux 2014) as well as genetic mutations. PubMed:29196815

Appears in Networks:
Annotations
Confidence
High

p(HGNC:APP, var("?")) increases path(MESH:"Alzheimer Disease") View Subject | View Object

More than 25 mutations in APP have been identified that are causative of the hereditary form of familial AD and a related condition of hereditary cerebral amyloid angiopathy. PubMed:18650430

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Confidence
Medium

a(HBP:HBP00067) negativeCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

A dramatically reduced ADAM10 protein level in the platelets of sporadic AD patients was also found to correlate with the significantly decreased sAPPalpha levels found in their platlets and cerebrospinal fluid [55] and the reduced alpha-secretase activity in the temporal cortex homogenates of AD patients [56] PubMed:21214928

Appears in Networks:
Annotations
Confidence
Medium
MeSH
Blood Platelets
MeSH
Cerebrospinal Fluid

a(MESH:Caspases) increases path(MESH:"Alzheimer Disease") View Subject | View Object

Cleavage of APP by caspases may also contribute to AD pathologies PubMed:21214928

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Confidence
Medium

p(HBP:HBP00065) positiveCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

There are reports showing that the protein and mRNA levels of KPI-containing APP isoforms are elevated in AD brain and associated with increased Ab deposition [9]; and prolonged activation of extrasynaptic NMDA receptor in neurons can shift APP expression from APP695 to KPI-containing APP isoforms, accompanied with increased production of Ab [10] PubMed:21214928

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Annotations
Confidence
Medium

p(HGNC:ADAM10) negativeCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

A dramatically reduced ADAM10 protein level in the platelets of sporadic AD patients was also found to correlate with the significantly decreased sAPPalpha levels found in their platlets and cerebrospinal fluid [55] and the reduced alpha-secretase activity in the temporal cortex homogenates of AD patients [56] PubMed:21214928

Appears in Networks:
Annotations
Confidence
Medium
MeSH
Blood Platelets

act(p(HGNC:ADAM10)) negativeCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

A dramatically reduced ADAM10 protein level in the platelets of sporadic AD patients was also found to correlate with the significantly decreased sAPPalpha levels found in their platlets and cerebrospinal fluid [55] and the reduced alpha-secretase activity in the temporal cortex homogenates of AD patients [56] PubMed:21214928

Appears in Networks:
Annotations
Confidence
Medium
MeSH
Temporal Lobe

p(HGNC:APP, frag("672_713")) increases path(MESH:"Alzheimer Disease") View Subject | View Object

Studies done on familial AD (FAD) mutations consistently show increases in the ratio of Abeta42/40 [105,144], suggesting that elevated levels of Abeta42 relative to Abeta40 is critical for AD pathogenesis, probably by providing the core for Abeta assembly into oligomers, fibrils and amyloidogenic plaques [145,146] PubMed:21214928

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MeSH
Endosomes
Confidence
High
MeSH
Neurons

r(HBP:HBP00064) positiveCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

There are reports showing that the protein and mRNA levels of KPI-containing APP isoforms are elevated in AD brain and associated with increased Ab deposition [9]; and prolonged activation of extrasynaptic NMDA receptor in neurons can shift APP expression from APP695 to KPI-containing APP isoforms, accompanied with increased production of Ab [10] PubMed:21214928

Appears in Networks:
Annotations
Confidence
Medium

a(HBP:HBP00064) positiveCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

The levels of APP isoforms with a KPI domain seem to be elevated in patients with AD (Menendez- Gonzalez et al. 2005) and a splicing shift in neurons from APP695 to KPI-containing APP isoforms, along with increased Abeta generation, is observed when the NMDA receptor is activated (Bordji et al. 2010) PubMed:22122372

Appears in Networks:
Annotations
Confidence
Medium
MeSH
Neurons

a(HBP:HBP00065) positiveCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

The levels of APP isoforms with a KPI domain seem to be elevated in patients with AD (Menendez- Gonzalez et al. 2005) and a splicing shift in neurons from APP695 to KPI-containing APP isoforms, along with increased Abeta generation, is observed when the NMDA receptor is activated (Bordji et al. 2010) PubMed:22122372

Appears in Networks:
Annotations
Confidence
Medium
MeSH
Neurons

a(MESH:"Amyloid beta-Peptides") association path(MESH:"Alzheimer Disease") View Subject | View Object

Plaques consisting of beta-amyloid (Abeta) peptide (Selkoe 1998), neurofibrillary tangles consisting largely of hyperphosphorylated microtubule-associated tau protein (Buee et al. 2000; Gendron and Petrucelli 2009) and neuron loss in the hippocampus and cortex regions are the major pathological hallmarks of Alzheimer’s disease. PubMed:22122372

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Annotations
Confidence
High

bp(GO:"neurofibrillary tangle assembly") association path(MESH:"Alzheimer Disease") View Subject | View Object

Plaques consisting of beta-amyloid (Abeta) peptide (Selkoe 1998), neurofibrillary tangles consisting largely of hyperphosphorylated microtubule-associated tau protein (Buee et al. 2000; Gendron and Petrucelli 2009) and neuron loss in the hippocampus and cortex regions are the major pathological hallmarks of Alzheimer’s disease. PubMed:22122372

Appears in Networks:
Annotations
Confidence
High

bp(GO:"neuron death") association path(MESH:"Alzheimer Disease") View Subject | View Object

Plaques consisting of beta-amyloid (Abeta) peptide (Selkoe 1998), neurofibrillary tangles consisting largely of hyperphosphorylated microtubule-associated tau protein (Buee et al. 2000; Gendron and Petrucelli 2009) and neuron loss in the hippocampus and cortex regions are the major pathological hallmarks of Alzheimer’s disease. PubMed:22122372

Appears in Networks:
Annotations
Confidence
High
MeSH
Cerebral Cortex
MeSH
Hippocampus

a(CHEBI:nicotine) causesNoChange path(MESH:"Alzheimer Disease") View Subject | View Object

In human trials, nicotine showed little efficacy in ameliorating AD symptoms (437). However, treatment was initiated after diagnosis of symptoms, and there is both epidemiological data and direct evidence from animal models that this is too late (106, 346, 396). PubMed:19126755

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Text Location
Review

bp(GO:"synaptic transmission, cholinergic") negativeCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

AD is the most common form of dementia in the elderly population. The histopathology of this disease is well known to have at least four components: 1) loss of cholinergic neurotransmission, 2) deposition of extracellular Abeta peptides into plaques, 3) hyperphosphorylation of the tau protein that leads to excessive formation of neurofibrillar tangles, and 4) increased local inflammation. PubMed:19126755

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Text Location
Review

bp(GO:cognition) negativeCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

Chronic alpha7 nAChR inhibition in the hippocampus by elevated levels of KYNA can contribute to auditory gating deficits, which appear to be associated with the development of schizophrenia (156). It is also feasible that KYNAinduced inhibition of alpha7 nAChRs contributes to the cognitive impairment observed in patients with AD and schizophrenia (273). PubMed:19126755

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MeSH
Hippocampus
Text Location
Review

act(p(HGNCGENEFAMILY:"Cholinergic receptors nicotinic subunits")) negativeCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

Reduced nAChR function/expression in the brain has been associated with the pathophysiology of catastrophic disorders, including AD and schizophrenia (discussed in later sections, and see Refs. 277, 432). PubMed:19126755

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Text Location
Review

p(HGNCGENEFAMILY:"Cholinergic receptors nicotinic subunits") negativeCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

However, loss of brain nAChRs precedes that of muscarinic receptors during normal aging, and it is often much more extensive in human brains afflicted with AD relative to age-matched controls (236, 308, 373, 374, 416, 519). In fact, alpha4 nAChR expression can decrease by >80% in the AD brain (306, 374). PubMed:19126755

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Text Location
Review

p(HGNCGENEFAMILY:"Cholinergic receptors nicotinic subunits") positiveCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

It is noteworthy that nAChR expression by astrocytes in brains afflicted with AD is increased (463, 518), and astrocytes in general have been reported to be more plentiful in the hippocampus of some rat strains with age (35, 284). PubMed:19126755

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MeSH
Astrocytes
Text Location
Review

p(HGNC:CHRNA7) negativeCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

In particular, the association of the alpha7 nAChR gene with a sensory gating deficit that is similar to attention deficits in patients with schizophrenia (157), and the degree of alpha4beta2 nAChR loss and altered alpha7 expresson correlate well with the magnitude of progressive cognitive decline in mild-to-moderate AD patients (46). PubMed:19126755

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Text Location
Review

p(HBP:"alpha-4 beta-2 nAChR") negativeCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

As will be returned to below, it is also the first nAChR subtype to exhibit measurable decline in expression in the aged mammalian brain and especially in neurodegenerative disorders such as AD (236, 374). PubMed:19126755

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Text Location
Review

p(HBP:"alpha-4 beta-2 nAChR") negativeCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

In particular, the association of the alpha7 nAChR gene with a sensory gating deficit that is similar to attention deficits in patients with schizophrenia (157), and the degree of alpha4beta2 nAChR loss and altered alpha7 expresson correlate well with the magnitude of progressive cognitive decline in mild-to-moderate AD patients (46). PubMed:19126755

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Text Location
Review

p(HGNC:CHRNA4) negativeCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

However, loss of brain nAChRs precedes that of muscarinic receptors during normal aging, and it is often much more extensive in human brains afflicted with AD relative to age-matched controls (236, 308, 373, 374, 416, 519). In fact, alpha4 nAChR expression can decrease by >80% in the AD brain (306, 374). PubMed:19126755

Appears in Networks:
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Text Location
Review

path(MESH:"Neurofibrillary Tangles") positiveCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

AD is the most common form of dementia in the elderly population. The histopathology of this disease is well known to have at least four components: 1) loss of cholinergic neurotransmission, 2) deposition of extracellular Abeta peptides into plaques, 3) hyperphosphorylation of the tau protein that leads to excessive formation of neurofibrillar tangles, and 4) increased local inflammation. PubMed:19126755

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Review

path(MESH:"Neurogenic Inflammation") positiveCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

AD is the most common form of dementia in the elderly population. The histopathology of this disease is well known to have at least four components: 1) loss of cholinergic neurotransmission, 2) deposition of extracellular Abeta peptides into plaques, 3) hyperphosphorylation of the tau protein that leads to excessive formation of neurofibrillar tangles, and 4) increased local inflammation. PubMed:19126755

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Text Location
Review

path(MESH:"Plaque, Amyloid") positiveCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

AD is the most common form of dementia in the elderly population. The histopathology of this disease is well known to have at least four components: 1) loss of cholinergic neurotransmission, 2) deposition of extracellular Abeta peptides into plaques, 3) hyperphosphorylation of the tau protein that leads to excessive formation of neurofibrillar tangles, and 4) increased local inflammation. PubMed:19126755

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Text Location
Review

path(MESH:Dementia) positiveCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

AD is the most common form of dementia in the elderly population. The histopathology of this disease is well known to have at least four components: 1) loss of cholinergic neurotransmission, 2) deposition of extracellular Abeta peptides into plaques, 3) hyperphosphorylation of the tau protein that leads to excessive formation of neurofibrillar tangles, and 4) increased local inflammation. PubMed:19126755

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Text Location
Review

a(CHEBI:"EC 3.1.1.8 (cholinesterase) inhibitor") decreases path(MESH:"Alzheimer Disease") View Subject | View Object

There is, however, a consensus that cholinesterase inhibitors perform measurably, but modestly, in slowing the progression of AD (Raina et al., 2008), one meta-analysis estimating their efficacy to amount to saving 2 months per year in the progression of the disease (Trinh et al., 2003). PubMed:19293145

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a(CHEBI:"amyloid-beta polypeptide 42") association path(MESH:"Alzheimer Disease") View Subject | View Object

An increasing ratio of the full-length, 1–42 peptide to the 1–40 form is associated with disease (Kumar-Singh et al., 2006), and mutations underlying familial forms of AD either increase this ratio or increase the amount of Abeta secreted. PubMed:19293145

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a(CHEBI:"amyloid-beta") increases path(MESH:"Alzheimer Disease") View Subject | View Object

It is generally agreed that the beta-amyloid peptide (Abeta) plays an important role in the development of AD. The brains of patients with AD contain deposits of Abeta, and Abeta is toxic to cultured neurons (Kihara et al., 1997a; Yao et al., 2005). In addition, mice transgenically overexpressing Abeta or with mutations that enhance Abeta aggregation show many of the symptoms of AD (Hsiao et al., 1996; van Groen et al., 2006). PubMed:19293145

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MeSH
Brain

sec(a(CHEBI:"amyloid-beta")) association path(MESH:"Alzheimer Disease") View Subject | View Object

An increasing ratio of the full-length, 1–42 peptide to the 1–40 form is associated with disease (Kumar-Singh et al., 2006), and mutations underlying familial forms of AD either increase this ratio or increase the amount of Abeta secreted. PubMed:19293145

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a(CHEBI:"amyloid-beta") association path(MESH:"Alzheimer Disease") View Subject | View Object

APP and APP/presenilin-1 (PS-1) mice do not show neurodegeneration (Irizarry et al., 1997) and yet show several features of AD, including accumulation of plaques and defects in learning (Hsiao et al., 1996), suggesting that many features of AD are not the result of neuronal loss. These animals nonetheless have swollen cholinergic nerve terminals at 12 months, suggesting defective nerve sprouting (Hernandez et al., 2001). PubMed:19293145

Appears in Networks:

path(MESH:"Plaque, Amyloid") positiveCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

AD is characterized pathologically by the occurrence of intracellular neurofibrillary tangles rich in tau protein and extracellular plaques containing amyloid peptides (Price et al., 1991). PubMed:19293145

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a(CHEBI:donepezil) decreases path(MESH:"Alzheimer Disease") View Subject | View Object

Current licensed pharmacological treatments for AD consist largely of three acetylcholinesterase (AChE) inhibitors: rivastigmine, galantamine, and donepezil (Aguglia et al., 2004; Ritchie et al., 2004), although memantine, a blocker of L-glutamate receptors of the Nmethyl- D-aspartate (NMDA) subtype, is also deployed in late stages of the disease PubMed:19293145

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a(CHEBI:galanthamine) decreases path(MESH:"Alzheimer Disease") View Subject | View Object

Current licensed pharmacological treatments for AD consist largely of three acetylcholinesterase (AChE) inhibitors: rivastigmine, galantamine, and donepezil (Aguglia et al., 2004; Ritchie et al., 2004), although memantine, a blocker of L-glutamate receptors of the Nmethyl- D-aspartate (NMDA) subtype, is also deployed in late stages of the disease PubMed:19293145

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a(CHEBI:memantine) decreases path(MESH:"Alzheimer Disease") View Subject | View Object

Current licensed pharmacological treatments for AD consist largely of three acetylcholinesterase (AChE) inhibitors: rivastigmine, galantamine, and donepezil (Aguglia et al., 2004; Ritchie et al., 2004), although memantine, a blocker of L-glutamate receptors of the Nmethyl- D-aspartate (NMDA) subtype, is also deployed in late stages of the disease PubMed:19293145

Appears in Networks:

a(CHEBI:rivastigmine) decreases path(MESH:"Alzheimer Disease") View Subject | View Object

Current licensed pharmacological treatments for AD consist largely of three acetylcholinesterase (AChE) inhibitors: rivastigmine, galantamine, and donepezil (Aguglia et al., 2004; Ritchie et al., 2004), although memantine, a blocker of L-glutamate receptors of the Nmethyl- D-aspartate (NMDA) subtype, is also deployed in late stages of the disease PubMed:19293145

Appears in Networks:

a(HBP:"alpha-4 beta-2 nAChR") association path(MESH:"Alzheimer Disease") View Subject | View Object

Genetic association studies investigating single nucleotide polymorphisms point to roles for cholinergic signaling components such as the synthetic enzyme ChAT, the inactivating enzyme AChE, and alpha4beta2 nAChRs in AD (Cook et al., 2004, 2005; Vasto et al., 2006). The most vulnerable neurons in AD seem to be those expressing high levels of nAChRs, particularly those containing the alpha7 subunit (D’Andrea and Nagele, 2006), and the numbers of nAChRs as well as some of their associated proteins change in AD (Martin-Ruiz et al., 1999; Gotti et al., 2006; Sabbagh et al., 2006). PubMed:19293145

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a(HBP:"amyloid-beta aggregates") association path(MESH:"Alzheimer Disease") View Subject | View Object

It is generally agreed that the beta-amyloid peptide (Abeta) plays an important role in the development of AD. The brains of patients with AD contain deposits of Abeta, and Abeta is toxic to cultured neurons (Kihara et al., 1997a; Yao et al., 2005). In addition, mice transgenically overexpressing Abeta or with mutations that enhance Abeta aggregation show many of the symptoms of AD (Hsiao et al., 1996; van Groen et al., 2006). PubMed:19293145

Appears in Networks:
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MeSH
Brain

a(MESH:"Neurofibrillary Tangles") positiveCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

AD is characterized pathologically by the occurrence of intracellular neurofibrillary tangles rich in tau protein and extracellular plaques containing amyloid peptides (Price et al., 1991). PubMed:19293145

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bp(GO:"regulation of cytosolic calcium ion concentration") association path(MESH:"Alzheimer Disease") View Subject | View Object

Recent research interest has focused on the role of calcium dyshomeostasis in AD (Green and LaFerla, 2008); for instance, genetic links with the regulation of cytosolic calcium have been identified (Dreses- Werringloer et al., 2008). Thus nAChRs may provide a link between Abeta and disruption of calcium homeostasis. PubMed:19293145

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bp(GO:learning) association path(MESH:"Alzheimer Disease") View Subject | View Object

APP and APP/presenilin-1 (PS-1) mice do not show neurodegeneration (Irizarry et al., 1997) and yet show several features of AD, including accumulation of plaques and defects in learning (Hsiao et al., 1996), suggesting that many features of AD are not the result of neuronal loss. These animals nonetheless have swollen cholinergic nerve terminals at 12 months, suggesting defective nerve sprouting (Hernandez et al., 2001). PubMed:19293145

Appears in Networks:

p(HGNC:CHRNA7) association path(MESH:"Alzheimer Disease") View Subject | View Object

Genetic association studies investigating single nucleotide polymorphisms point to roles for cholinergic signaling components such as the synthetic enzyme ChAT, the inactivating enzyme AChE, and alpha4beta2 nAChRs in AD (Cook et al., 2004, 2005; Vasto et al., 2006). The most vulnerable neurons in AD seem to be those expressing high levels of nAChRs, particularly those containing the alpha7 subunit (D’Andrea and Nagele, 2006), and the numbers of nAChRs as well as some of their associated proteins change in AD (Martin-Ruiz et al., 1999; Gotti et al., 2006; Sabbagh et al., 2006). PubMed:19293145

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act(p(HGNCGENEFAMILY:"Cholinergic receptors nicotinic subunits")) association path(MESH:"Alzheimer Disease") View Subject | View Object

Thus, although other mechanisms are also involved in the development of AD, there is abundant evidence that defects in cholinergic synaptic transmission and, in particular, nAChR-mediated signaling plays a major role in the disease and are hence the subject of attempts to generate new routes to therapy. PubMed:19293145

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g(HGNC:ACHE) association path(MESH:"Alzheimer Disease") View Subject | View Object

Genetic association studies investigating single nucleotide polymorphisms point to roles for cholinergic signaling components such as the synthetic enzyme ChAT, the inactivating enzyme AChE, and alpha4beta2 nAChRs in AD (Cook et al., 2004, 2005; Vasto et al., 2006). The most vulnerable neurons in AD seem to be those expressing high levels of nAChRs, particularly those containing the alpha7 subunit (D’Andrea and Nagele, 2006), and the numbers of nAChRs as well as some of their associated proteins change in AD (Martin-Ruiz et al., 1999; Gotti et al., 2006; Sabbagh et al., 2006). PubMed:19293145

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g(HGNC:APOE) positiveCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

The apolipoprotein E type 4 allele (APOE-epsilon4) encodes the APOE lipoprotein, which through its lipid transport function plays a role in lipid metabolism. APOE-epsilon4 has been found to be a major risk factor for late familial or sporadic AD, with a strong gene-dosage effect such that the number of APOE-epsilon4 alleles correlated positively with the risk of developing AD and the age of onset (Corder et al., 1993). PubMed:19293145

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g(HGNC:CHAT) association path(MESH:"Alzheimer Disease") View Subject | View Object

Genetic association studies investigating single nucleotide polymorphisms point to roles for cholinergic signaling components such as the synthetic enzyme ChAT, the inactivating enzyme AChE, and alpha4beta2 nAChRs in AD (Cook et al., 2004, 2005; Vasto et al., 2006). The most vulnerable neurons in AD seem to be those expressing high levels of nAChRs, particularly those containing the alpha7 subunit (D’Andrea and Nagele, 2006), and the numbers of nAChRs as well as some of their associated proteins change in AD (Martin-Ruiz et al., 1999; Gotti et al., 2006; Sabbagh et al., 2006). PubMed:19293145

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act(p(HGNC:INS)) association path(MESH:"Alzheimer Disease") View Subject | View Object

Shortterm nicotine application also induces phosphorylation of p44/42MAPK, p38MAPK, and STAT-3 and was mediated mostly by alpha7 nAChRs in rat vascular smooth muscle cells (Wada et al., 2007). It is noteworthy that the JAK-2/STAT-3 pathway also mediates the mitogenic effects of insulin, a process recently implicated in AD (Li and Ho¨lscher, 2007). PubMed:19293145

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Cell Ontology (CL)
vascular associated smooth muscle cell

p(HGNC:PSEN1) association path(MESH:"Alzheimer Disease") View Subject | View Object

APP and APP/presenilin-1 (PS-1) mice do not show neurodegeneration (Irizarry et al., 1997) and yet show several features of AD, including accumulation of plaques and defects in learning (Hsiao et al., 1996), suggesting that many features of AD are not the result of neuronal loss. These animals nonetheless have swollen cholinergic nerve terminals at 12 months, suggesting defective nerve sprouting (Hernandez et al., 2001). PubMed:19293145

Appears in Networks:

path(MESH:"Cognitive Dysfunction") association path(MESH:"Alzheimer Disease") View Subject | View Object

It has long been known that cognitive decline in AD correlates well with synaptic loss (Lue et al., 1999), and it has been shown directly that soluble Abeta inhibits synaptic plasticity (Rowan et al., 2004). PubMed:19293145

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path(MESH:"Plaque, Amyloid") biomarkerFor path(MESH:"Alzheimer Disease") View Subject | View Object

The accumulation of plaques consisting of Abeta is one of the histopathological hallmarks of AD. Abeta is the product of serial cleavage of the amyloid precursor protein (APP) first by beta and then by gamma secretases to yield Abeta peptides of varying lengths, predominantly the 37-, 40-, and 42- residue forms. PubMed:19293145

Appears in Networks:

path(MESH:"Plaque, Amyloid") association path(MESH:"Alzheimer Disease") View Subject | View Object

APP and APP/presenilin-1 (PS-1) mice do not show neurodegeneration (Irizarry et al., 1997) and yet show several features of AD, including accumulation of plaques and defects in learning (Hsiao et al., 1996), suggesting that many features of AD are not the result of neuronal loss. These animals nonetheless have swollen cholinergic nerve terminals at 12 months, suggesting defective nerve sprouting (Hernandez et al., 2001). PubMed:19293145

Appears in Networks:

path(MESH:Death) association path(MESH:"Alzheimer Disease") View Subject | View Object

Alzheimer’s disease (AD) is the most common form of dementia in elderly persons. It is a neurodegenerative disease marked by decline in memory and cognitive performance, including deterioration of language as well as defects in visual and motor coordination, and eventual death (for review, see Cummings, 2004). PubMed:19293145

Appears in Networks:

path(MESH:Dementia) association path(MESH:"Alzheimer Disease") View Subject | View Object

Alzheimer’s disease (AD) is the most common form of dementia in elderly persons. It is a neurodegenerative disease marked by decline in memory and cognitive performance, including deterioration of language as well as defects in visual and motor coordination, and eventual death (for review, see Cummings, 2004). PubMed:19293145

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bp(GO:cognition) association path(MESH:"Alzheimer Disease") View Subject | View Object

Conversely, the most commonly associated symptoms of AD are cognitive in nature and include deficits in learning and memory. However, 50%–80% of AD patients display psychotic and behavioral disturbances that are correlated with poor social and functional outcomes PubMed:24511233

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bp(GO:learning) association path(MESH:"Alzheimer Disease") View Subject | View Object

Conversely, the most commonly associated symptoms of AD are cognitive in nature and include deficits in learning and memory. However, 50%–80% of AD patients display psychotic and behavioral disturbances that are correlated with poor social and functional outcomes PubMed:24511233

Appears in Networks:

bp(GO:memory) association path(MESH:"Alzheimer Disease") View Subject | View Object

Conversely, the most commonly associated symptoms of AD are cognitive in nature and include deficits in learning and memory. However, 50%–80% of AD patients display psychotic and behavioral disturbances that are correlated with poor social and functional outcomes PubMed:24511233

Appears in Networks:

bp(MESH:Aging) association path(MESH:"Alzheimer Disease") View Subject | View Object

Age is the primary risk factor for AD, and the disease usually manifests in individuals after the age of 60 years. Due to an aging population, the prevalence of AD is predicted to rise to 66 million people by the year 2030. PubMed:24511233

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path(MESH:"Cognitive Dysfunction") association path(MESH:"Alzheimer Disease") View Subject | View Object

Schizophrenia (SZ) and Alzheimer’s disease (AD) are two devastating disorders of the central nervous system (CNS) that present clinically with cognitive impairments and psychotic symptoms PubMed:24511233

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MeSH
Central Nervous System

path(MESH:"Cognitive Dysfunction") association path(MESH:"Alzheimer Disease") View Subject | View Object

AD is the most commonly diagnosed form of dementia and currently affects approximately 35 million individuals worldwide.7 AD is a progressive neurodegenerative disease that is characterized by a host of cognitive deficits, including impairments in learning and memory. In addition to the well-documented cognitive impairments, AD patients also display behavioral disturbances, including anxiety, depression, and psychosis PubMed:24511233

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path(MESH:"Neurofibrillary Tangles") biomarkerFor path(MESH:"Alzheimer Disease") View Subject | View Object

The hallmarks of AD pathology are the accumulation of amyloid-beta (Abeta) peptide aggregates (neuritic plaques) and hyperphosphorylated tau protein (neurofibrillary tangles). PubMed:24511233

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path(MESH:"Plaque, Amyloid") biomarkerFor path(MESH:"Alzheimer Disease") View Subject | View Object

The hallmarks of AD pathology are the accumulation of amyloid-beta (Abeta) peptide aggregates (neuritic plaques) and hyperphosphorylated tau protein (neurofibrillary tangles). PubMed:24511233

Appears in Networks:

path(MESH:"Psychotic Disorders") association path(MESH:"Alzheimer Disease") View Subject | View Object

Schizophrenia (SZ) and Alzheimer’s disease (AD) are two devastating disorders of the central nervous system (CNS) that present clinically with cognitive impairments and psychotic symptoms PubMed:24511233

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MeSH
Central Nervous System

path(MESH:"Psychotic Disorders") association path(MESH:"Alzheimer Disease") View Subject | View Object

Conversely, the most commonly associated symptoms of AD are cognitive in nature and include deficits in learning and memory. However, 50%–80% of AD patients display psychotic and behavioral disturbances that are correlated with poor social and functional outcomes PubMed:24511233

Appears in Networks:

path(MESH:"Psychotic Disorders") association path(MESH:"Alzheimer Disease") View Subject | View Object

AD is the most commonly diagnosed form of dementia and currently affects approximately 35 million individuals worldwide.7 AD is a progressive neurodegenerative disease that is characterized by a host of cognitive deficits, including impairments in learning and memory. In addition to the well-documented cognitive impairments, AD patients also display behavioral disturbances, including anxiety, depression, and psychosis PubMed:24511233

Appears in Networks:

path(MESH:Dementia) association path(MESH:"Alzheimer Disease") View Subject | View Object

AD is the most commonly diagnosed form of dementia and currently affects approximately 35 million individuals worldwide.7 AD is a progressive neurodegenerative disease that is characterized by a host of cognitive deficits, including impairments in learning and memory. In addition to the well-documented cognitive impairments, AD patients also display behavioral disturbances, including anxiety, depression, and psychosis PubMed:24511233

Appears in Networks:

a(CHEBI:"EC 3.1.1.7 (acetylcholinesterase) inhibitor") decreases path(MESH:"Alzheimer Disease") View Subject | View Object

The most commonly prescribed treatments for AD are acetylcholinesterase inhibitors, which decrease the hydrolysis rate of ACh and, thereby, enhance cholinergic signaling. One such drug, galantamine (Reminyl), also potentiates nAChRs (66). PubMed:17009926

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Annotations
MeSH
Alzheimer Disease

bp(GO:"neuron death") positiveCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

The most well-appreciated neuronal loss, however, is in the cholinergic system (155, 156), particularly the basal forebrain cholinergic system comprised of the medial septal nucleus, the horizontal and vertical diagonal bands of Broca, and the nucleus basalis of Meynert (157). PubMed:17009926

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Annotations
Cell Ontology (CL)
cholinergic neuron
MeSH
Alzheimer Disease

bp(GO:"neuron death") positiveCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

As AD worsens, cholinergic neurons are progressively lost and the number of nAChRs declines, particularly in the hippocampus and cortex (140, 158). PubMed:17009926

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Annotations
Cell Ontology (CL)
cholinergic neuron
MeSH
Cerebral Cortex
MeSH
Hippocampus
MeSH
Alzheimer Disease

complex(a(CHEBI:"amyloid-beta polypeptide 42"), p(HGNC:CHRNA7)) association path(MESH:"Alzheimer Disease") View Subject | View Object

Although Aβ peptides negatively alter the cholinergic system at multiple sites, including ACh synthesis, ACh release, and muscarinic receptors (157), the discovery that Aβ1−42 binds to α7 nAChRs with high affinity suggested the potential for a causal role of nAChRs in AD (159, 160). PubMed:17009926

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MeSH
Alzheimer Disease

p(FPLX:CHRN) association path(MESH:"Alzheimer Disease") View Subject | View Object

Decline, disruption, or alterations of nicotinic cholinergic mechanisms have been implicated in various dysfunctions, such as schizophrenia, epilepsy, autism, Alzheimer’s disease (AD), and addiction (17–23). PubMed:17009926

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act(p(FPLX:CHRN)) negativeCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

Nicotinic mechanisms contribute to cognitive function, and the decline of nicotinic mechanisms or loss of nAChRs has been observed in AD, dementia with Lewy bodies, Down syndrome, autism, and Parkinson’s disease (20, 140). PubMed:17009926

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p(FPLX:CHRN) negativeCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

Nicotinic mechanisms contribute to cognitive function, and the decline of nicotinic mechanisms or loss of nAChRs has been observed in AD, dementia with Lewy bodies, Down syndrome, autism, and Parkinson’s disease (20, 140). PubMed:17009926

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p(FPLX:CHRN) negativeCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

As AD worsens, cholinergic neurons are progressively lost and the number of nAChRs declines, particularly in the hippocampus and cortex (140, 158). PubMed:17009926

Appears in Networks:
Annotations
Cell Ontology (CL)
cholinergic neuron
MeSH
Cerebral Cortex
MeSH
Hippocampus
MeSH
Alzheimer Disease

a(CHEBI:rivastigmine) negativeCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

Rivastigmine has also been used for AD treatment due to its ease of use (transdermal patch) and good tolerability by patients PubMed:26813123

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Annotations
MeSH
Alzheimer Disease

a(MESH:"Basal Nucleus of Meynert") negativeCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

The loss of the nucleus basalis cholinergic neurons in AD patients is severe: from about 500,000 in the healthy adult to less than 100,000 in patients displaying advanced AD PubMed:26813123

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a(MESH:"Cholinergic Neurons") negativeCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

Further highlighting the importance of the cholinergic system in the CNS, cholinergic neuronal loss, especially in the basal forebrain, occurs not only in AD, but also in Parkinson’s disease [190, 191], Down syndrome [192], amyotrophic lateral sclerosis [193, 194], progressive supranuclear palsy [195, 196], and olivopontocerebellar atrophy [197] PubMed:26813123

Appears in Networks:
Annotations
MeSH
Basal Forebrain
MeSH
Central Nervous System

bp(GO:"synaptic transmission, cholinergic") association path(MESH:"Alzheimer Disease") View Subject | View Object

Because ACh has an important role in cognitive processes, the cholinergic system is pointed as an important factor in many forms of dementia, including AD PubMed:26813123

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p(HGNC:ACHE) association path(MESH:"Alzheimer Disease") View Subject | View Object

Furthermore, some evidences also suggest the involvement of AChE in the pathogenesis of AD PubMed:26813123

Appears in Networks:

complex(p(HGNC:CHRM1), p(INTERPRO:"G-protein alpha subunit, group Q")) negativeCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

It has been demonstrated that M1 muscarinic receptors coupling to G-proteins is impaired in the neocortex of AD patients and that the extent of M1/G-protein uncoupling is related to the severity of cognitive symptoms in AD PubMed:26813123

Appears in Networks:
Annotations
MeSH
Neocortex
MeSH
Alzheimer Disease

path(MESH:"Cognitive Dysfunction") positiveCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

In addition to cognitive alterations, psychiatric symptoms are frequently observed in AD patients, including apathy and depression PubMed:26813123

Appears in Networks:
Annotations
MeSH
CA3 Region, Hippocampal

path(MESH:Apathy) positiveCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

In addition to cognitive alterations, psychiatric symptoms are frequently observed in AD patients, including apathy and depression PubMed:26813123

Appears in Networks:
Annotations
MeSH
CA3 Region, Hippocampal

path(MESH:Depression) positiveCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

In addition to cognitive alterations, psychiatric symptoms are frequently observed in AD patients, including apathy and depression PubMed:26813123

Appears in Networks:
Annotations
MeSH
CA3 Region, Hippocampal

a(HBP:"amyloid-beta aggregates") increases path(MESH:"Alzheimer Disease") View Subject | View Object

Senile plaques consist of deposits of small peptides called beta-amyloid (Abeta). Multiple lines of evidence suggest that the overproduction/ aggregation of neurotoxic Abeta in vulnerable brain regions is the primary cause of AD PubMed:24590577

Appears in Networks:

p(HGNCGENEFAMILY:"Cholinergic receptors muscarinic") association path(MESH:"Alzheimer Disease") View Subject | View Object

Recent evidence indicates that cholinergic hypofunction is closely linked to Abeta and tau pathologies[20]. As a major receptor group for ACh, mAChRs have also been implicated in the pathophysiology of AD. PubMed:24590577

Appears in Networks:

path(MESH:"Neurofibrillary Tangles") association path(MESH:"Alzheimer Disease") View Subject | View Object

Alzheimer’s disease (AD) is a debilitating neurodegenerative disorder afflicting millions of people. It is diagnosed by the progressive loss of cognitive function and behavioral defi cits and is characterized by the presence of neurofibrillary tangles (NFTs), senile plaques, cholinergic neuron loss, and neuronal atrophy at autopsy PubMed:24590577

Appears in Networks:

path(MESH:"Plaque, Amyloid") association path(MESH:"Alzheimer Disease") View Subject | View Object

Alzheimer’s disease (AD) is a debilitating neurodegenerative disorder afflicting millions of people. It is diagnosed by the progressive loss of cognitive function and behavioral defi cits and is characterized by the presence of neurofibrillary tangles (NFTs), senile plaques, cholinergic neuron loss, and neuronal atrophy at autopsy PubMed:24590577

Appears in Networks:

a(CHEBI:"amyloid-beta") positiveCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

With the progression of the disease the amount of Abeta increases, it starts to accumulate, and becomes toxic for the neurons (Hernandez et al., 2010) PubMed:25514383

Appears in Networks:
Annotations
MeSH
Alzheimer Disease

a(GO:synapse) negativeCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

Dementia is a debilitating condition frequent in ageing populations, and Alzheimer's Disease (AD) accounts for 70% of all dementia cases. AD is characterized by neuropathological hallmarks consisting of an accumulation of Amyloid beta peptide (Ab) in extracellular plaques, intracellular deposits of tau protein, neuronal loss and, more recently, a prominent synaptic loss was identified (Braak and Braak,1991; Masliah et al., 2001; Selkoe,1991; Spires-Jones and Hyman, 2014) PubMed:25514383

Appears in Networks:

a(HBP:"amyloid-beta aggregates") positiveCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

With the progression of the disease the amount of Abeta increases, it starts to accumulate, and becomes toxic for the neurons (Hernandez et al., 2010) PubMed:25514383

Appears in Networks:
Annotations
MeSH
Alzheimer Disease

a(HP:"cholinergic neuron") negativeCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

In addition, anatomical studies in AD patients showed a massive loss of brain white matter and a specific reduction of cholinergic neurons of the basal forebrain (Auld et al., 2002; Bowen et al., 1976; Coyle et al., 1983; Kim et al., 2013; Whitehouse et al., 1981, 1982) PubMed:25514383

Appears in Networks:
Annotations
MeSH
Basal Forebrain

a(MESH:"White Matter") negativeCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

In addition, anatomical studies in AD patients showed a massive loss of brain white matter and a specific reduction of cholinergic neurons of the basal forebrain (Auld et al., 2002; Bowen et al., 1976; Coyle et al., 1983; Kim et al., 2013; Whitehouse et al., 1981, 1982) PubMed:25514383

Appears in Networks:
Annotations
MeSH
Brain

bp(GO:"neuron death") positiveCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

Dementia is a debilitating condition frequent in ageing populations, and Alzheimer's Disease (AD) accounts for 70% of all dementia cases. AD is characterized by neuropathological hallmarks consisting of an accumulation of Amyloid beta peptide (Ab) in extracellular plaques, intracellular deposits of tau protein, neuronal loss and, more recently, a prominent synaptic loss was identified (Braak and Braak,1991; Masliah et al., 2001; Selkoe,1991; Spires-Jones and Hyman, 2014) PubMed:25514383

Appears in Networks:

complex(p(HGNC:CHRNA7), p(HGNC:FLNA)) positiveCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

Wang et al. showed that the association between FLNA and the alpha7 subunit is elevated in AD samples compared to age matched controls PubMed:25514383

Appears in Networks:

p(HGNC:MAPT) positiveCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

Dementia is a debilitating condition frequent in ageing populations, and Alzheimer's Disease (AD) accounts for 70% of all dementia cases. AD is characterized by neuropathological hallmarks consisting of an accumulation of Amyloid beta peptide (Ab) in extracellular plaques, intracellular deposits of tau protein, neuronal loss and, more recently, a prominent synaptic loss was identified (Braak and Braak,1991; Masliah et al., 2001; Selkoe,1991; Spires-Jones and Hyman, 2014) PubMed:25514383

Appears in Networks:

path(MESH:"Plaque, Amyloid") positiveCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

Dementia is a debilitating condition frequent in ageing populations, and Alzheimer's Disease (AD) accounts for 70% of all dementia cases. AD is characterized by neuropathological hallmarks consisting of an accumulation of Amyloid beta peptide (Ab) in extracellular plaques, intracellular deposits of tau protein, neuronal loss and, more recently, a prominent synaptic loss was identified (Braak and Braak,1991; Masliah et al., 2001; Selkoe,1991; Spires-Jones and Hyman, 2014) PubMed:25514383

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path(MESH:Dementia) association path(MESH:"Alzheimer Disease") View Subject | View Object

Dementia is a debilitating condition frequent in ageing populations, and Alzheimer's Disease (AD) accounts for 70% of all dementia cases. AD is characterized by neuropathological hallmarks consisting of an accumulation of Amyloid beta peptide (Ab) in extracellular plaques, intracellular deposits of tau protein, neuronal loss and, more recently, a prominent synaptic loss was identified (Braak and Braak,1991; Masliah et al., 2001; Selkoe,1991; Spires-Jones and Hyman, 2014) PubMed:25514383

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a(HBP:HBP00018) association path(MESH:"Alzheimer Disease") View Subject | View Object

AD is a chronic neurodegenerative disease characterized by the progressive deposition of the amyloid b (Ab) in the parenchyma of the brain. PubMed:21718217

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Confidence
High

a(HBP:HBP00030) positiveCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

The ApoE4 allele is most important genetic risk factor for AD, while the ApoE2 allele is thought to be protective. PubMed:21718217

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Confidence
High
MeSH
Microglia

act(p(HGNC:NR1H3)) increases path(MESH:"Alzheimer Disease") View Subject | View Object

In the past decade, drugs targeting the NRs, peroxisome proliferator-activated receptor g (PPARg) and liver X receptor (LXR) have shown to ameliorate pathogenesis in animal models of AD. PubMed:21718217

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Confidence
High
MeSH
Microglia

p(HBP:HBP00030) association path(MESH:"Alzheimer Disease") View Subject | View Object

The ApoE4 allele is most important genetic risk factor for AD, while the ApoE2 allele is thought to be protective. PubMed:21718217

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Confidence
Medium

act(p(HGNC:PPARG)) increases path(MESH:"Alzheimer Disease") View Subject | View Object

In the past decade, drugs targeting the NRs, peroxisome proliferator-activated receptor g (PPARg) and liver X receptor (LXR) have shown to ameliorate pathogenesis in animal models of AD. PubMed:21718217

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Confidence
High
MeSH
Microglia

r(HGNC:ARG1) positiveCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

In this study, it was shown that samples from human AD brains as well as two aged mouse models of AD showed increased mRNA levels of the M2 markers, Arg1 and Ym1, when compared to age matched controls [101]. PubMed:21718217

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Confidence
High

r(HGNC:CHI3L1) positiveCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

In this study, it was shown that samples from human AD brains as well as two aged mouse models of AD showed increased mRNA levels of the M2 markers, Arg1 and Ym1, when compared to age matched controls [101]. PubMed:21718217

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Confidence
High

a(CHEBI:"amyloid-beta") increases path(MESH:"Alzheimer Disease") View Subject | View Object

beta-Amyloid (Abeta) is also an important factor, which may initiate and promote AD (Selkoe 1999) PubMed:11230871

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a(CHEBI:estrogen) decreases path(MESH:"Alzheimer Disease") View Subject | View Object

Estrogen, which in epidemiologic studies has been shown to reduce the risk of AD (Henderson 1997), has in experimental studies in PC 12 cells shown neuroprotective effects against Abeta toxicity that are at least partly mediated by the alpha7 subtype nAChR (Svensson and Nordberg 1998) PubMed:11230871

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MeSH
Alzheimer Disease

a(HBP:"alpha-4-containing nAChR") negativeCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

A decrease in protein levels of the alpha4 nAChR but not of the alpha3 and alpha7 nAChRs was reported by Martin-Ruiz et al (1999) PubMed:11230871

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a(HBP:"alpha-7-containing nAChR") negativeCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

Lee et al (2000) recently also reported a significant decrease in the alpha7 nAChR protein level of the AD hippocampus PubMed:11230871

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MeSH
Hippocampus

bp(GO:cognition) negativeCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

A progressive loss of cortical acetylcholinesterase activity has been observed in AD patients with cognitive decline (Shinotoh et al 2000) PubMed:11230871

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MeSH
Cerebral Cortex

p(FPLX:CHRN) association path(MESH:"Alzheimer Disease") View Subject | View Object

The nAChRs are found to be involved in a complex range of central nervous system disorders including Alzheimer’s disease (AD), Parkinson’s disease, schizophrenia, Tourette’s syndrome, anxiety, depression, and epilepsy (Newhouse and Kelton 2000; Newhouse et al 1997; Paterson and Nordberg 2000) PubMed:11230871

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p(FPLX:CHRN) negativeCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

A consistent, significant loss of nAChRs has been observed in cortical autopsy brain tissue from AD patients relative to age-matched healthy subjects (Nordberg and Winblad 1986) PubMed:11230871

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MeSH
Cerebral Cortex
MeSH
Alzheimer Disease

p(HGNC:CHRNA4) negativeCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

A decrease in the protein levels of the alpha3 and alpha4 nAChR subunits was recently measured in the temporal cortex and of the alpha3, alpha4, and alpha7 nAChR subtypes in the hippocampi of AD brains relative to age-matched control subjects (Guan et al 2000b) PubMed:11230871

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MeSH
Temporal Lobe

p(HGNC:CHRNA7) negativeCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

A decrease in the protein levels of the alpha3 and alpha4 nAChR subunits was recently measured in the temporal cortex and of the alpha3, alpha4, and alpha7 nAChR subtypes in the hippocampi of AD brains relative to age-matched control subjects (Guan et al 2000b) PubMed:11230871

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MeSH
Hippocampus

act(p(HGNC:ACHE)) negativeCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

A progressive loss of cortical acetylcholinesterase activity has been observed in AD patients with cognitive decline (Shinotoh et al 2000) PubMed:11230871

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MeSH
Cerebral Cortex

p(HGNC:CHRNA3) negativeCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

When the laminar binding distribution of [3H]nicotine, [3H]epibatidine, and [3H]cytisine was measured in AD cortical autopsy tissue, marked reductions were observed relative to control brains (Sihver et al 1999c) (Figure 1) PubMed:11230871

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MeSH
Cerebral Cortex
MeSH
Alzheimer Disease

p(HGNC:CHRNA3) negativeCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

A decrease in the protein levels of the alpha3 and alpha4 nAChR subunits was recently measured in the temporal cortex and of the alpha3, alpha4, and alpha7 nAChR subtypes in the hippocampi of AD brains relative to age-matched control subjects (Guan et al 2000b) PubMed:11230871

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MeSH
Temporal Lobe

r(HGNC:CHRNA7) positiveCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

Examination of the regional expression of mRNA of the nAChR alpha4 and alpha3 subunits has shown no difference in autopsy AD brain tissue in any region analyzed (Hellstro ¨m-Lindahl et al 1999; Terzano et al 1998), whereas the level of the alpha7 mRNA was significantly higher in the hippocampus (Hellstro¨m-Lindahl et al 1999) PubMed:11230871

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MeSH
Hippocampus

p(MGI:Chrna7) negativeCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

Post hoc analysis revealed that, levels of the a7 nAChR protein in normal saline-treated AD mice were significantly lower than its level in the control animals (p<0.001). PubMed:25881725

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p(HGNC:CHRNA7) negativeCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

Reduction of α7 AChRs in the CNS is linked with Alzheimer dis- ease, which has been shown to lead to neuronal loss [53,188–190]. PubMed:22040696

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MeSH
Central Nervous System

a(HBP:AβOs) association path(MESH:"Alzheimer Disease") View Subject | View Object

a4b2-nAChRs have been implicated in nicotine self-administration, reward, and depen- dence, and in diseases such as Alzheimer’s and epilepsy [1–5,27–33]. PubMed:21787755

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p(MESH:"Receptors, Nicotinic") association path(MESH:"Alzheimer Disease") View Subject | View Object

nAChRs contribute to cognitive function, and changes in their number and/or func- tion are associated with various pathological conditions such as cognitive disorders, anxiety, depression, Alzheimer’s and Parkinson’s disease, pain and epilepsy PubMed:28901280

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p(HGNC:MAPT, pmod(Ph, Tyr, 394)) positiveCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

The phosphorylation of tau at Tyr394 and Tyr18 is present in PHFs in the brains of individuals with AD. PubMed:26631930

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a(CHEBI:"amyloid-beta") association path(MESH:"Alzheimer Disease") View Subject | View Object

Taken together, several lines of evidence point to a reduced UPS function in AD and suggest that both Abeta and tau are important players in the game. PubMed:14556719

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bp(GO:"proteasome-mediated ubiquitin-dependent protein catabolic process") negativeCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

Taken together, several lines of evidence point to a reduced UPS function in AD and suggest that both Abeta and tau are important players in the game. PubMed:14556719

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act(p(HGNC:UBA2)) negativeCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

Finally, there is also evidence for a reduced activity of E1 and E2 enzymes in cerebral cortex samples from AD patients compared to age-matched controls (Lopez Salon et al., 2000). PubMed:14556719

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MeSH
Cerebral Cortex

act(p(HGNC:UBA1)) negativeCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

Finally, there is also evidence for a reduced activity of E1 and E2 enzymes in cerebral cortex samples from AD patients compared to age-matched controls (Lopez Salon et al., 2000). PubMed:14556719

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MeSH
Cerebral Cortex

composite(a(CHEBI:"amyloid-beta"), p(HGNC:MAPT, var("?"))) increases path(MESH:"Alzheimer Disease") View Subject | View Object

Mutant tau alone does not cause AD, favoring the idea that accumulation of erroneously processed Abeta is a key event in AD pathogenesis PubMed:14556719

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p(HGNC:MAPT) association path(MESH:"Alzheimer Disease") View Subject | View Object

Taken together, several lines of evidence point to a reduced UPS function in AD and suggest that both Abeta and tau are important players in the game. PubMed:14556719

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p(HGNC:APP, var("?")) increases path(MESH:"Alzheimer Disease") View Subject | View Object

They have demonstrated that AD can be caused by mutations in the APP gene, either in the vicinity of the secretase cleavage sites, causing abnormal APP processing, or in the sequence coding for Abeta, giving rise to a peptide that is more likely to self-aggregate PubMed:14556719

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a(CHEBI:sirolimus) decreases path(MESH:"Alzheimer Disease") View Subject | View Object

Treatment of cell, Drosophila, and mouse models of HD, SCA3/MJD, AD, PD, and ALS with the mTOR inhibitor rapamycin (or a derivative) reduces aggregation and suppresses disease (140– 143). PubMed:25784053

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Cell Ontology (CL)
motor neuron

bp(GO:macroautophagy) negativeCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

Consistent with a role of autophagy in disease, AD patient tissues exhibit impaired initiation of macroautophagy and an excess of autophagic vacuoles in dystrophic neurites, possibly due to impaired targeting of the vacuolar ATPase to the lysosome (86, 87). PubMed:25784053

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act(p(FPLX:Proteasome)) negativeCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

Experiments examining the effects of Aβ on proteasomal activity in vitro revealed an inhibitory effect on the chymotrypsin-like properties of the 20S core (73), consistent with observations of impaired proteasome function in AD patient brains (74). PubMed:25784053

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MeSH
Brain

p(HGNC:SERPINF2) negativeCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

However, the levels and activity of plasmin are reduced in AD brains (Ledesma et al. 2000) PubMed:29626319

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p(HGNC:CDK5) positiveCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

Thus, we now know three kinases, cdk5, MAP kinase, and GSK-3, all of which are present in neurons, which are capable of transforming tau into the Alzheimer-like state, and therefore could account for the pathological phosphorylation of tau in Alzheimer brains PubMed:8282104

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Confidence
High
MeSH
Neurons

p(FPLX:ERK) positiveCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

Thus, we now know three kinases, cdk5, MAP kinase, and GSK-3, all of which are present in neurons, which are capable of transforming tau into the Alzheimer-like state, and therefore could account for the pathological phosphorylation of tau in Alzheimer brains PubMed:8282104

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Confidence
High
MeSH
Neurons

p(FPLX:GSK3) positiveCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

Thus, we now know three kinases, cdk5, MAP kinase, and GSK-3, all of which are present in neurons, which are capable of transforming tau into the Alzheimer-like state, and therefore could account for the pathological phosphorylation of tau in Alzheimer brains PubMed:8282104

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Confidence
High
MeSH
Neurons

p(HGNC:MAPT, pmod(Ph)) positiveCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

Thus, we now know three kinases, cdk5, MAP kinase, and GSK-3, all of which are present in neurons, which are capable of transforming tau into the Alzheimer-like state, and therefore could account for the pathological phosphorylation of tau in Alzheimer brains PubMed:8282104

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Confidence
High
MeSH
Neurons

a(CHEBI:"selenium(2+)") negativeCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

Selenium deficits have been linked to AD, and thus it is interesting that seleno- methionine boosted ALN flux, from AMPK recruit- ment through autophagosome formation to lysosomal degradation, in the 3×Tg AD mouse model 112 . PubMed:30116051

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MeSH
Dopaminergic Neurons

a(HBP:HBP00030) increases path(MESH:"Alzheimer Disease") View Subject | View Object

Third, apolipoprotein E allele 4 (APOE4), a major risk allele for sporadic AD, is associated with increased generation and accumula- tion of Aβ42 (REFS59,60) . PubMed:30116051

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MeSH
Alzheimer Disease

g(HGNC:PSEN1, var("?")) positiveCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

Fourth, genetic mutations and anomalies of presenilin 1, a dominant negative gene linked to AD, are associated with reduced lysosomal v-ATPase-mediated acidifica- tion 40,63 , a compromised ALN and deficient mitophagy 64 . PubMed:30116051

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MeSH
Alzheimer Disease

p(HGNC:MAPT, var("?")) positiveCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

Truncation of Tau by caspases and endopeptidases has been suggested to constitute an important pathogenic step in AD PubMed:29215007

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Confidence
High

a(MESH:Lysosomes) positiveCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

This demonstrates that in the absence of mutant PS1, AD-associated impairment in autophagy occurs and thus is due to other factors. Treatment of ex vivo hippocampal slice cultures with lysosomal disruptors causes the formation of enlarged, dystrophic neurites filled with AVs and lysosomes, similar to what is seen in mouse AD models and human AD tissue (85, 86) PubMed:24027553

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Text Location
Review

bp(GO:"proteasomal protein catabolic process") negativeCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

The accumulation of proteins in AD patients’ brains generated interest in the role of proteasomal function. There is evidence suggesting that proteasomal activity, but not protein level, is decreased in AD-sensitive brain regions specifically compared to unaffected regions (68, 69). PubMed:24027553

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Text Location
Review

bp(HBP:"APP processing") association path(MESH:"Alzheimer Disease") View Subject | View Object

Another serine protease recently implicated in tau processing is HTRA1. This is a ubiquitously expressed, ATP-independent intracellular protease. Expression is detectable in many tissues, including the nervous system, although expression is low (40).Nonetheless, this enzyme was initially implicated in AD because it may play a role in amyloid processing (41). PubMed:24027553

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Review

bp(MESH:Autophagy) positiveCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

This demonstrates that in the absence of mutant PS1, AD-associated impairment in autophagy occurs and thus is due to other factors. Treatment of ex vivo hippocampal slice cultures with lysosomal disruptors causes the formation of enlarged, dystrophic neurites filled with AVs and lysosomes, similar to what is seen in mouse AD models and human AD tissue (85, 86) PubMed:24027553

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Text Location
Review

p(HGNC:MAPT) association path(MESH:"Alzheimer Disease") View Subject | View Object

Insoluble, fibrillar intraneuronal accumulations of pathological forms of the tau protein called neurofibrillary tangles (NFTs) are important and defining hallmarks of the Alzheimer disease (AD) brain. Indeed, the progression of AD can be neuropathologically staged based on the location and extent of tau pathology (1). PubMed:24027553

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Text Location
Review

p(HGNC:MAPT) association path(MESH:"Alzheimer Disease") View Subject | View Object

Even though the modifications of tau that are the primary contributors to toxicity have not been conclusively determined, it is clear that tau plays an essential role in the pathogenesis of AD. PubMed:24027553

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Text Location
Review

act(p(HGNC:CASP3)) positiveCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

In order for caspase to cleave tau in the AD brain, it needs to be present in its active form. The active forms of both caspase-3 and caspase-6 are elevated in AD-specific brain regions (temporal and frontal lobes) compared to unaffected regions (cerebellum) and control brains (57, 58). PubMed:24027553

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MeSH
Frontal Lobe
MeSH
Temporal Lobe
Text Location
Review

act(p(HGNC:CASP6)) positiveCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

In order for caspase to cleave tau in the AD brain, it needs to be present in its active form. The active forms of both caspase-3 and caspase-6 are elevated in AD-specific brain regions (temporal and frontal lobes) compared to unaffected regions (cerebellum) and control brains (57, 58). PubMed:24027553

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MeSH
Frontal Lobe
MeSH
Temporal Lobe
Text Location
Review

p(HGNC:PIN1) association path(MESH:"Alzheimer Disease") View Subject | View Object

For example, it has been shown that the isomerase Pin1, which has been implicated in AD (30), had opposite effects on P301L and wild-type tau degradation (31). An alternative explanation for the effects of PSA may be that PSA is indirectly regulating tau degradation. PubMed:24027553

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Review

path(MESH:"Neurofibrillary Tangles") positiveCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

Insoluble, fibrillar intraneuronal accumulations of pathological forms of the tau protein called neurofibrillary tangles (NFTs) are important and defining hallmarks of the Alzheimer disease (AD) brain. Indeed, the progression of AD can be neuropathologically staged based on the location and extent of tau pathology (1). PubMed:24027553

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Text Location
Review

path(MESH:Inflammation) positiveCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

First, inflammation, which is a common feature of AD, may contribute to tau pathology by activating caspases. Treating cells with the prostaglandin cyclopentenone byproduct PGJ2 increased caspase activity and increased cleaved tau (62). PubMed:24027553

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Review

a(HBP:"3R tau") positiveCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

The band patterns in the immunoblots showed that the AD cases contained a mixture of isoforms, the PiD cases clearly contained 3R isoforms but also some 4R isoforms, while the vast majority of pathology in CBD cases were comprised of 4R tau isoforms PubMed:27574109

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a(HBP:"4R tau") positiveCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

The band patterns in the immunoblots showed that the AD cases contained a mixture of isoforms, the PiD cases clearly contained 3R isoforms but also some 4R isoforms, while the vast majority of pathology in CBD cases were comprised of 4R tau isoforms PubMed:27574109

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a(HBP:"Tau oligomers") positiveCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

Similarly, the soluble fraction from AD contained the greatest level of TOC1 reactivity, followed by CBD and then PiD had the lowest signal (Fig. 6D; one-way ANOVA with Holm-Sidak post-hoc, F(2,9) = 16.57, p = 0.001) PubMed:27574109

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a(HBP:"Tau oligomers") positiveCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

TOC1 detected significantly more oligomeric tau in AD compared to CBD and PiD and more in CBD compared to PiD (Fig. 6G; one-way ANOVA with Holm-Sidak post-hoc, F(2,9) = 35.32, p < 0.0001) PubMed:27574109

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a(HBP:"phosphatase-activating domain") positiveCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

In contrast, AD soluble tau displayed the highest level of TNT1 followed by CBD, with PiD having the lowest levels (Fig. 6C; one-way ANOVA with Holm-Sidak post-hoc, F(2,9) = 24.87, p = 0.0002). PubMed:27574109

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composite(a(HBP:"phosphatase-activating domain"), p(HGNC:MAPT)) positiveCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

TNT1 detected significantly more PAD exposed tau in AD compared to PiD, and more in CBD when compared to PiD, but AD and CBD were not different (Fig. 6F; one-way ANOVA with Holm-Sidak post-hoc, F(2,9) = 12.07, p = 0.0028) PubMed:27574109

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p(HGNC:MAPT) positiveCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

Total tau levels in the soluble fractions were similar for AD, CBD and PiD, as indicated by the Tau5 sandwich ELISA (Fig. 6B; one-way ANOVA, F(2,9) = 3.283, p = 0.085) PubMed:27574109

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p(HGNC:MAPT) positiveCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

Total tau levels in the insoluble fractions, as detected by Tau5, were highest in AD, followed by CBD and PiD contained the least (Fig. 6E; one-way ANOVA with Holm-Sidak post-hoc, F(2,9) = 25.93, p = 0.0002) PubMed:27574109

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p(HGNC:MAPT, pmod(HBP:hyperphosphorylation)) positiveCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

AD brains could induce AD-type tau hyperphosphorylation. Consistent with the results obtained with synthetic ADDLs, we found that treatment of mature hippocampal neuronal cultures with a soluble AD brain extract led to a significant increase in P231 tau phosphorylation (Fig. 6D) compared to cultures treated with a non-AD brain extract (Fig. 6A). PubMed:17403556

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Text Location
Results

p(HGNC:MAPT, pmod(Ph, Thr, 231)) positiveCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

Following exposure to ADDLs, double-label immunofluorescence microscopy showed high levels of tau phosphorylated at Thr231, which discriminates among AD and non-AD subjects and patients with other forms of dementia (Hampel et al., 2004, 2003), in neurons with prominent dendritic ADDL binding (detected with NU1, Fig. 2K–M). ADDL binding to synaptic hot-spots in hippocampal neurons is evident in images at highermagnification (60×objective, PanelsLand M). PubMed:17403556

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Text Location
Results

act(p(HBP:"6D tau", frag("2_18"))) association path(MESH:"Alzheimer Disease") View Subject | View Object

These data indicated that increased PAD exposure, as revealed by TNT1 immunoreac- tivity, occurs early in AD and remains present throughout the disease process. PubMed:21734277

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act(p(HBP:"6D tau", frag("2_18"))) association path(MESH:"Alzheimer Disease") View Subject | View Object

Together, these data suggest that increased PAD exposure represents an early event in AD pathogenesis and that AT8 may not be required for PAD ex- posure in situ. PubMed:21734277

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bp(MESH:Aging) increases path(MESH:"Alzheimer Disease") View Subject | View Object

Aging, a major risk factor for AD, affects both the UPS and autophagy. PubMed:23528736

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p(HBP:"UBB+1") positiveCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

A Ub with a 19-residue C-terminal extension from the UBB gene, or UBB+1 (Fig.2A) is selectively expressed in the brains of AD patients (van Leeuwen et al.,1998) and is often found to be accumulated in NFT in Alzheimer’s disease and other tauopathies PubMed:23528736

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MeSH
Brain

p(HGNC:RPS27A) positiveCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

The levels of Ub in AD brain appear to be significantly increased ( Kudo et al., 71 1994 ). PubMed:23528736

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p(HGNC:UBA52) positiveCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

The levels of Ub in AD brain appear to be significantly increased ( Kudo et al., 71 1994 ). PubMed:23528736

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p(HGNC:UBB) positiveCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

The levels of Ub in AD brain appear to be significantly increased ( Kudo et al., 71 1994 ). PubMed:23528736

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p(HGNC:UBC) positiveCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

The levels of Ub in AD brain appear to be significantly increased ( Kudo et al., 71 1994 ). PubMed:23528736

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p(HGNC:UCHL1, var("?")) association path(MESH:"Alzheimer Disease") View Subject | View Object

Mutations in ubiquitin C-terminal hydrolase L1 (UCH-L1) have been proposed to have a role in various neurodegenerative diseases including AD, although the causality of mutations in this gene in Parkinson’s disease is now considered doubtful (Healy et al., 2006; Hutter et al., 2008). PubMed:23528736

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p(HGNCGENEFAMILY:"Ubiquitin conjugating enzymes E2") negativeCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

Interestingly, E1 and E2 enzymes have been reported to be downregulated in AD (de Vrij et al., 2004) (Fig. 2B). PubMed:23528736

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p(HGNCGENEFAMILY:"Ubiquitin like modifier activating enzymes") negativeCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

Interestingly, E1 and E2 enzymes have been reported to be downregulated in AD (de Vrij et al., 2004) (Fig. 2B). PubMed:23528736

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p(HGNC:BAG1) positiveCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

BAG1 is upregulated in the hippocampus of AD patients [130], where it associates with tau and increases tau levels in cooperation with Hsp70 [131] PubMed:21882945

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MeSH
Hippocampus

p(HGNC:MAPT, pmod(Ph, Ser, 202), pmod(Ph, Thr, 205)) positiveCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

However, this issue is more complicated, as other work has shown that chemical inhibition of Hsp90 by 17-AAG and other inhibitors reduces cellular levels of two phospho- tau species, pS202/T205 and pS396/S404, both of which are relevant to AD pathogenesis [119]. PubMed:21882945

Appears in Networks:

p(HGNC:MAPT, pmod(Ph, Ser, 396), pmod(Ph, Ser, 404)) positiveCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

However, this issue is more complicated, as other work has shown that chemical inhibition of Hsp90 by 17-AAG and other inhibitors reduces cellular levels of two phospho- tau species, pS202/T205 and pS396/S404, both of which are relevant to AD pathogenesis [119]. PubMed:21882945

Appears in Networks:

bp(MESH:"Cerebrovascular Circulation") association path(MESH:"Alzheimer Disease") View Subject | View Object

Aberrant cerebral blood flow is a functional defect that occurs in AD and tauNFT mice, and is closely associated with cognitive impairment (Wells et al., 2015) PubMed:30126037

Appears in Networks:
Annotations
Confidence
High
MeSH
Neurons

p(HGNC:MAPT) association path(MESH:"Alzheimer Disease") View Subject | View Object

Tau protein accumulation is the most common pathology among degenerative brain diseases, including Alzheimer’s disease (AD), progressive supranuclear palsy (PSP), traumatic brain injury (TBI) and over twenty others PubMed:30126037

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Annotations
Confidence
High

a(GO:"neurofibrillary tangle") positiveCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

Compared to non-demented controls, AD brains exhibit up to 50% of neuronal loss in the cortex, exceeding the number of NFTs (Gómez-Isla et al., 1997) PubMed:28420982

Appears in Networks:
Annotations
Confidence
Medium
MeSH
Cerebral Cortex

a(HBP:"Tau oligomers") positiveCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

The onset of clinical symptoms in AD and PSP brains correlate with elevated levels of tau oligomer (Maeda et al., 2006, 2007; Patterson et al., 2011; Lasagna-Reeves et al., 2012b; Gerson et al., 2014a) PubMed:28420982

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Annotations
Confidence
Medium
MeSH
Cerebral Cortex

bp(GO:"neuron death") positiveCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

Compared to non-demented controls, AD brains exhibit up to 50% of neuronal loss in the cortex, exceeding the number of NFTs (Gómez-Isla et al., 1997) PubMed:28420982

Appears in Networks:
Annotations
Confidence
Medium
MeSH
Cerebral Cortex

p(HGNC:MAPT) positiveCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

In AD, the quantity of tau identified in the CSF increases with disease progression (Hampel et al., 2010). However, the mechanism of tau propagation from the brain to the CSF remains elusive PubMed:28420982

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Annotations
Confidence
Medium
MeSH
Cerebrospinal Fluid

p(HGNC:MAPT) positiveCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

More recently, patients affected with FTD and AD, were found to have high levels of total tau and phosphorylated tau (p-T181 and p-S396; Saman et al., 2012) PubMed:28420982

Appears in Networks:
Annotations
Confidence
Medium
MeSH
Cerebrospinal Fluid
MeSH
Alzheimer Disease

p(HGNC:MAPT, pmod(Ph, Ser, 396)) positiveCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

More recently, patients affected with FTD and AD, were found to have high levels of total tau and phosphorylated tau (p-T181 and p-S396; Saman et al., 2012) PubMed:28420982

Appears in Networks:
Annotations
Confidence
Medium
MeSH
Cerebrospinal Fluid
MeSH
Alzheimer Disease

p(HGNC:MAPT, pmod(Ph, Thr, 181)) positiveCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

More recently, patients affected with FTD and AD, were found to have high levels of total tau and phosphorylated tau (p-T181 and p-S396; Saman et al., 2012) PubMed:28420982

Appears in Networks:
Annotations
Confidence
Medium
MeSH
Cerebrospinal Fluid
MeSH
Alzheimer Disease

a(PUBCHEM:4456430) decreases path(MESH:"Alzheimer Disease") View Subject | View Object

Interestingly, one study demonstrated that patients chronically treated with FK506, which inhibits the PPIase domain of many of the FKBPs, significantly reduced the incidence of AD (Taglialatela et al., 2015). PubMed:29311797

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p(HGNC:AHSA1) positiveCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

Aha1 levels have been shown to increase with AD. PubMed:29311797

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Annotations
MeSH
Cerebral Cortex

p(HGNC:MAPT, pmod(Ph)) association path(MESH:"Alzheimer Disease") View Subject | View Object

Studies have shown that PP5 is able to dephosphorylate tau at several phosphorylation sites connected to AD pathology (Gong et al., 2004). PubMed:29311797

Appears in Networks:
Annotations
MeSH
Cerebral Cortex

p(HGNC:STUB1) association path(MESH:"Alzheimer Disease") View Subject | View Object

CHIP has been linked to several neurodegenerative disorders including Huntington’s disease, Parkinson’s disease and AD as well as other diseases such as cystic fibrosis and cancer (Dickey et al., 2007b; Edkins, 2015). PubMed:29311797

Appears in Networks:
Annotations
MeSH
Cerebral Cortex

p(HGNC:MAPT, pmod(Ph, Ser, 113)) positiveCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

3. Putative phosphorylation sites on tau protein and epitopes specific for major tau antibodies. Red color denotes amino acids phosphorylation in AD brain. PubMed:26751493

Appears in Networks:
Annotations
MeSH
Alzheimer Disease

p(HGNC:MAPT, pmod(Ph, Ser, 185)) positiveCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

3. Putative phosphorylation sites on tau protein and epitopes specific for major tau antibodies. Red color denotes amino acids phosphorylation in AD brain. PubMed:26751493

Appears in Networks:
Annotations
MeSH
Alzheimer Disease

p(HGNC:MAPT, pmod(Ph, Ser, 191)) positiveCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

3. Putative phosphorylation sites on tau protein and epitopes specific for major tau antibodies. Red color denotes amino acids phosphorylation in AD brain. PubMed:26751493

Appears in Networks:
Annotations
MeSH
Alzheimer Disease

p(HGNC:MAPT, pmod(Ph, Ser, 208)) positiveCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

3. Putative phosphorylation sites on tau protein and epitopes specific for major tau antibodies. Red color denotes amino acids phosphorylation in AD brain. PubMed:26751493

Appears in Networks:
Annotations
MeSH
Alzheimer Disease

p(HGNC:MAPT, pmod(Ph, Ser, 210)) positiveCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

3. Putative phosphorylation sites on tau protein and epitopes specific for major tau antibodies. Red color denotes amino acids phosphorylation in AD brain. PubMed:26751493

Appears in Networks:
Annotations
MeSH
Alzheimer Disease

p(HGNC:MAPT, pmod(Ph, Ser, 214)) positiveCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

3. Putative phosphorylation sites on tau protein and epitopes specific for major tau antibodies. Red color denotes amino acids phosphorylation in AD brain. PubMed:26751493

Appears in Networks:
Annotations
MeSH
Alzheimer Disease

p(HGNC:MAPT, pmod(Ph, Ser, 237)) positiveCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

3. Putative phosphorylation sites on tau protein and epitopes specific for major tau antibodies. Red color denotes amino acids phosphorylation in AD brain. PubMed:26751493

Appears in Networks:
Annotations
MeSH
Alzheimer Disease

p(HGNC:MAPT, pmod(Ph, Ser, 238)) positiveCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

3. Putative phosphorylation sites on tau protein and epitopes specific for major tau antibodies. Red color denotes amino acids phosphorylation in AD brain. PubMed:26751493

Appears in Networks:
Annotations
MeSH
Alzheimer Disease

p(HGNC:MAPT, pmod(Ph, Ser, 258)) positiveCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

3. Putative phosphorylation sites on tau protein and epitopes specific for major tau antibodies. Red color denotes amino acids phosphorylation in AD brain. PubMed:26751493

Appears in Networks:
Annotations
MeSH
Alzheimer Disease

p(HGNC:MAPT, pmod(Ph, Ser, 262)) positiveCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

3. Putative phosphorylation sites on tau protein and epitopes specific for major tau antibodies. Red color denotes amino acids phosphorylation in AD brain. PubMed:26751493

Appears in Networks:
Annotations
MeSH
Alzheimer Disease

p(HGNC:MAPT, pmod(Ph, Ser, 289)) positiveCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

3. Putative phosphorylation sites on tau protein and epitopes specific for major tau antibodies. Red color denotes amino acids phosphorylation in AD brain. PubMed:26751493

Appears in Networks:
Annotations
MeSH
Alzheimer Disease

p(HGNC:MAPT, pmod(Ph, Ser, 356)) positiveCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

3. Putative phosphorylation sites on tau protein and epitopes specific for major tau antibodies. Red color denotes amino acids phosphorylation in AD brain. PubMed:26751493

Appears in Networks:
Annotations
MeSH
Alzheimer Disease

p(HGNC:MAPT, pmod(Ph, Ser, 409)) positiveCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

3. Putative phosphorylation sites on tau protein and epitopes specific for major tau antibodies. Red color denotes amino acids phosphorylation in AD brain. PubMed:26751493

Appears in Networks:
Annotations
MeSH
Alzheimer Disease

p(HGNC:MAPT, pmod(Ph, Ser, 422)) positiveCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

3. Putative phosphorylation sites on tau protein and epitopes specific for major tau antibodies. Red color denotes amino acids phosphorylation in AD brain. PubMed:26751493

Appears in Networks:
Annotations
MeSH
Alzheimer Disease

p(HGNC:MAPT, pmod(Ph, Ser, 433)) positiveCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

3. Putative phosphorylation sites on tau protein and epitopes specific for major tau antibodies. Red color denotes amino acids phosphorylation in AD brain. PubMed:26751493

Appears in Networks:
Annotations
MeSH
Alzheimer Disease

p(HGNC:MAPT, pmod(Ph, Ser, 435)) positiveCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

3. Putative phosphorylation sites on tau protein and epitopes specific for major tau antibodies. Red color denotes amino acids phosphorylation in AD brain. PubMed:26751493

Appears in Networks:
Annotations
MeSH
Alzheimer Disease

p(HGNC:MAPT, pmod(Ph, Ser, 68)) positiveCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

3. Putative phosphorylation sites on tau protein and epitopes specific for major tau antibodies. Red color denotes amino acids phosphorylation in AD brain. PubMed:26751493

Appears in Networks:
Annotations
MeSH
Alzheimer Disease

p(HGNC:MAPT, pmod(Ph, Thr, 123)) positiveCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

3. Putative phosphorylation sites on tau protein and epitopes specific for major tau antibodies. Red color denotes amino acids phosphorylation in AD brain. PubMed:26751493

Appears in Networks:
Annotations
MeSH
Alzheimer Disease

p(HGNC:MAPT, pmod(Ph, Thr, 153)) positiveCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

3. Putative phosphorylation sites on tau protein and epitopes specific for major tau antibodies. Red color denotes amino acids phosphorylation in AD brain. PubMed:26751493

Appears in Networks:
Annotations
MeSH
Alzheimer Disease

p(HGNC:MAPT, pmod(Ph, Thr, 175)) positiveCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

3. Putative phosphorylation sites on tau protein and epitopes specific for major tau antibodies. Red color denotes amino acids phosphorylation in AD brain. PubMed:26751493

Appears in Networks:
Annotations
MeSH
Alzheimer Disease

p(HGNC:MAPT, pmod(Ph, Thr, 184)) positiveCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

3. Putative phosphorylation sites on tau protein and epitopes specific for major tau antibodies. Red color denotes amino acids phosphorylation in AD brain. PubMed:26751493

Appears in Networks:
Annotations
MeSH
Alzheimer Disease

p(HGNC:MAPT, pmod(Ph, Thr, 403)) positiveCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

3. Putative phosphorylation sites on tau protein and epitopes specific for major tau antibodies. Red color denotes amino acids phosphorylation in AD brain. PubMed:26751493

Appears in Networks:
Annotations
MeSH
Alzheimer Disease

p(HGNC:MAPT, pmod(Ph, Thr, 427)) positiveCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

3. Putative phosphorylation sites on tau protein and epitopes specific for major tau antibodies. Red color denotes amino acids phosphorylation in AD brain. PubMed:26751493

Appears in Networks:
Annotations
MeSH
Alzheimer Disease

p(HGNC:MAPT, pmod(Ph, Thr, 69)) positiveCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

3. Putative phosphorylation sites on tau protein and epitopes specific for major tau antibodies. Red color denotes amino acids phosphorylation in AD brain. PubMed:26751493

Appears in Networks:
Annotations
MeSH
Alzheimer Disease

p(HGNC:MAPT, pmod(Ph, Thr, 71)) positiveCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

3. Putative phosphorylation sites on tau protein and epitopes specific for major tau antibodies. Red color denotes amino acids phosphorylation in AD brain. PubMed:26751493

Appears in Networks:
Annotations
MeSH
Alzheimer Disease

p(HGNC:MAPT, pmod(Ph, Tyr, 18)) positiveCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

3. Putative phosphorylation sites on tau protein and epitopes specific for major tau antibodies. Red color denotes amino acids phosphorylation in AD brain. PubMed:26751493

Appears in Networks:
Annotations
MeSH
Alzheimer Disease

p(HGNC:MAPT, pmod(Ph, Tyr, 197)) positiveCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

3. Putative phosphorylation sites on tau protein and epitopes specific for major tau antibodies. Red color denotes amino acids phosphorylation in AD brain. PubMed:26751493

Appears in Networks:
Annotations
MeSH
Alzheimer Disease

p(HGNC:MAPT, pmod(Ph, Tyr, 394)) positiveCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

3. Putative phosphorylation sites on tau protein and epitopes specific for major tau antibodies. Red color denotes amino acids phosphorylation in AD brain. PubMed:26751493

Appears in Networks:
Annotations
MeSH
Alzheimer Disease

g(HGNC:APP, var("?")) association path(MESH:"Alzheimer Disease") View Subject | View Object

When characterized by autosomal dominant inheritance, EOAD is related to mutations in the presenilin 1 (PSEN1), presenilin 2 (PSEN2) or amyloid precursor protein (APP) genes. PubMed:26195256

Appears in Networks:

p(HGNC:MAPT, pmod(Ph)) positiveCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

However, the AD brain extract (3,000g) contained significantly higher levels of phosphorylated tau (Fig. 6h,i,m) when compared with the control brain, especially those associated with some specific phosphorylation sites such as pS199, pS396 and pS404 (Fig. 6i). PubMed:26458742

Appears in Networks:
Annotations
Confidence
High
MeSH
Brain

p(HGNC:MAPT, pmod(Ph, Ser, 199)) positiveCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

However, the AD brain extract (3,000g) contained significantly higher levels of phosphorylated tau (Fig. 6h,i,m) when compared with the control brain, especially those associated with some specific phosphorylation sites such as pS199, pS396 and pS404 (Fig. 6i). PubMed:26458742

Appears in Networks:
Annotations
Confidence
High
MeSH
Brain

p(HGNC:MAPT, pmod(Ph, Ser, 396)) positiveCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

However, the AD brain extract (3,000g) contained significantly higher levels of phosphorylated tau (Fig. 6h,i,m) when compared with the control brain, especially those associated with some specific phosphorylation sites such as pS199, pS396 and pS404 (Fig. 6i). PubMed:26458742

Appears in Networks:
Annotations
Confidence
High
MeSH
Brain

p(HGNC:MAPT, pmod(Ph, Ser, 404)) positiveCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

However, the AD brain extract (3,000g) contained significantly higher levels of phosphorylated tau (Fig. 6h,i,m) when compared with the control brain, especially those associated with some specific phosphorylation sites such as pS199, pS396 and pS404 (Fig. 6i). PubMed:26458742

Appears in Networks:
Annotations
Confidence
High
MeSH
Brain

a(CHEBI:"amyloid-beta polypeptide 40") association path(MESH:"Alzheimer Disease") View Subject | View Object

Given the size of AD-related proteins, mono- meric Aβ1-40, Aβ1-42 and tau, should be able to pass freely through astrocytic endfeet clefts at the glial barrier.72 PubMed:26195256

Appears in Networks:

a(CHEBI:"amyloid-beta polypeptide 42") association path(MESH:"Alzheimer Disease") View Subject | View Object

Given the size of AD-related proteins, mono- meric Aβ1-40, Aβ1-42 and tau, should be able to pass freely through astrocytic endfeet clefts at the glial barrier.72 PubMed:26195256

Appears in Networks:

a(MESH:"Cerebral Cortex") association path(MESH:"Alzheimer Disease") View Subject | View Object

The gross pathological changes consist of brain atrophy, particularly in the hippocampal formation, temporal lobes and parietotemporal cortices, accompanied by cortical thinning, enlarged ventricles and white matter abnormalities, as evident on MRI. PubMed:26195256

Appears in Networks:

a(MESH:"Cerebral Ventricles") association path(MESH:"Alzheimer Disease") View Subject | View Object

The gross pathological changes consist of brain atrophy, particularly in the hippocampal formation, temporal lobes and parietotemporal cortices, accompanied by cortical thinning, enlarged ventricles and white matter abnormalities, as evident on MRI. PubMed:26195256

Appears in Networks:

a(MESH:"Prefrontal Cortex") association path(MESH:"Alzheimer Disease") View Subject | View Object

The gross pathological changes consist of brain atrophy, particularly in the hippocampal formation, temporal lobes and parietotemporal cortices, accompanied by cortical thinning, enlarged ventricles and white matter abnormalities, as evident on MRI. PubMed:26195256

Appears in Networks:

a(MESH:"White Matter") association path(MESH:"Alzheimer Disease") View Subject | View Object

The gross pathological changes consist of brain atrophy, particularly in the hippocampal formation, temporal lobes and parietotemporal cortices, accompanied by cortical thinning, enlarged ventricles and white matter abnormalities, as evident on MRI. PubMed:26195256

Appears in Networks:

g(HGNC:PSEN1, var("?")) association path(MESH:"Alzheimer Disease") View Subject | View Object

When characterized by autosomal dominant inheritance, EOAD is related to mutations in the presenilin 1 (PSEN1), presenilin 2 (PSEN2) or amyloid precursor protein (APP) genes. PubMed:26195256

Appears in Networks:

g(HGNC:PSEN2, var("?")) association path(MESH:"Alzheimer Disease") View Subject | View Object

When characterized by autosomal dominant inheritance, EOAD is related to mutations in the presenilin 1 (PSEN1), presenilin 2 (PSEN2) or amyloid precursor protein (APP) genes. PubMed:26195256

Appears in Networks:

p(HBP:"APOE e4") association path(MESH:"Alzheimer Disease") View Subject | View Object

The strongest identified genetic risk factor for LOAD is the apolipoprotein E (APOE) ε4 allele (APOE*ε4), PubMed:26195256

Appears in Networks:

p(HGNC:CLU) association path(MESH:"Alzheimer Disease") View Subject | View Object

although genome-wide association studies have linked LOAD to several other genetic variants, such as TREM2 (triggering receptor expressed on myeloid cells 2),27 clusterin (CLU),28 and phosphatidylinositol-binding clathrin assembly protein (PICALM).28,29 PubMed:26195256

Appears in Networks:

p(HGNC:PICALM) association path(MESH:"Alzheimer Disease") View Subject | View Object

although genome-wide association studies have linked LOAD to several other genetic variants, such as TREM2 (triggering receptor expressed on myeloid cells 2),27 clusterin (CLU),28 and phosphatidylinositol-binding clathrin assembly protein (PICALM).28,29 PubMed:26195256

Appears in Networks:

p(HGNC:TREM2) association path(MESH:"Alzheimer Disease") View Subject | View Object

although genome-wide association studies have linked LOAD to several other genetic variants, such as TREM2 (triggering receptor expressed on myeloid cells 2),27 clusterin (CLU),28 and phosphatidylinositol-binding clathrin assembly protein (PICALM).28,29 PubMed:26195256

Appears in Networks:

path(MESH:"Cardiovascular Diseases") association path(MESH:"Alzheimer Disease") View Subject | View Object

Known envi- ronmental risk factors for LOAD include cardiovascular disease, and factors conferring a risk of cardiovascu- lar disease, such as diabetes mellitus and hypertension. Head trauma, physical and mental inactivity, and sleep impairment are additional risk factors for LOAD PubMed:26195256

Appears in Networks:

path(MESH:"Craniocerebral Trauma") association path(MESH:"Alzheimer Disease") View Subject | View Object

Known envi- ronmental risk factors for LOAD include cardiovascular disease, and factors conferring a risk of cardiovascu- lar disease, such as diabetes mellitus and hypertension. Head trauma, physical and mental inactivity, and sleep impairment are additional risk factors for LOAD PubMed:26195256

Appears in Networks:

path(MESH:"Diabetes Mellitus") association path(MESH:"Alzheimer Disease") View Subject | View Object

Known envi- ronmental risk factors for LOAD include cardiovascular disease, and factors conferring a risk of cardiovascu- lar disease, such as diabetes mellitus and hypertension. Head trauma, physical and mental inactivity, and sleep impairment are additional risk factors for LOAD PubMed:26195256

Appears in Networks:

path(MESH:"Pick Disease of the Brain") association path(MESH:"Alzheimer Disease") View Subject | View Object

The gross pathological changes consist of brain atrophy, particularly in the hippocampal formation, temporal lobes and parietotemporal cortices, accompanied by cortical thinning, enlarged ventricles and white matter abnormalities, as evident on MRI. PubMed:26195256

Appears in Networks:

path(MESH:"Sleep Initiation and Maintenance Disorders") association path(MESH:"Alzheimer Disease") View Subject | View Object

Known envi- ronmental risk factors for LOAD include cardiovascular disease, and factors conferring a risk of cardiovascu- lar disease, such as diabetes mellitus and hypertension. Head trauma, physical and mental inactivity, and sleep impairment are additional risk factors for LOAD PubMed:26195256

Appears in Networks:

path(MESH:"Sleep Initiation and Maintenance Disorders") increases path(MESH:"Alzheimer Disease") View Subject | View Object

These findings might partly explain why sleep impairment increases the risk of AD PubMed:26195256

Appears in Networks:
Annotations
MeSH
Hippocampus
MeSH
Temporal Lobe

path(MESH:Aging) association path(MESH:"Alzheimer Disease") View Subject | View Object

Various factors have been reported to positively and negatively modulate the risk of LOAD. Specifically, the greatest overall risk factor for LOAD is ageing; PubMed:26195256

Appears in Networks:

path(MESH:Hypertension) association path(MESH:"Alzheimer Disease") View Subject | View Object

Known envi- ronmental risk factors for LOAD include cardiovascular disease, and factors conferring a risk of cardiovascu- lar disease, such as diabetes mellitus and hypertension. Head trauma, physical and mental inactivity, and sleep impairment are additional risk factors for LOAD PubMed:26195256

Appears in Networks:

a(HBP:"Tau aggregates") positiveCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

The amount of total tau captured with pS422 (detected with the pan-tau antibody, Tau5) was significantly higher in AD compared to control (Fig. 7E; t10 = 6.07, p = 0.0001). The level of pS422 tau that also contained PAD exposed tau (i.e., TNT1 reactive) was significantly higher in AD compared to control (Fig. 7F; t10 = 2.31, p = 0.0435). Similarly, the level of pS422 tau that also contained an oligomeric conformation (i.e., TOC1 reactive) was significantly higher in AD compared to control (Fig. 7G; t10 = 1.51, p = 0.0029). PubMed:27373205

Appears in Networks:

p(HGNC:MAPT, pmod(Ph)) positiveCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

The amount of total tau captured with pS422 (detected with the pan-tau antibody, Tau5) was significantly higher in AD compared to control (Fig. 7E; t10 = 6.07, p = 0.0001). The level of pS422 tau that also contained PAD exposed tau (i.e., TNT1 reactive) was significantly higher in AD compared to control (Fig. 7F; t10 = 2.31, p = 0.0435). Similarly, the level of pS422 tau that also contained an oligomeric conformation (i.e., TOC1 reactive) was significantly higher in AD compared to control (Fig. 7G; t10 = 1.51, p = 0.0029). PubMed:27373205

Appears in Networks:

a(GO:"neurofibrillary tangle") association path(MESH:"Alzheimer Disease") View Subject | View Object

AD (Alzheimer’s disease) is a progressive neurodegenerative disorder characterized by the extracellular accumulation of senile plaques composed of Aβ (amyloid β-peptide) and the intracellular accumulation of the MAP (microtubuleassociated protein) tau into both non-filamentous and filamentous inclusions, such as NFTs (neurofibrillary tangles), NTs (neuropil threads) and NPs (neuritic plaques) [1,2] PubMed:22817713

Appears in Networks:
Annotations
Confidence
Medium
MeSH
Intracellular Space

a(HBP:"Tau aggregates") positiveCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

AD (Alzheimer’s disease) is a progressive neurodegenerative disorder characterized by the extracellular accumulation of amyloid beta-peptide and the intracellular accumulation of tau PubMed:22817713

Appears in Networks:
Annotations
Confidence
Medium
MeSH
Intracellular Space

a(HBP:"amyloid-beta aggregates") positiveCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

AD (Alzheimer’s disease) is a progressive neurodegenerative disorder characterized by the extracellular accumulation of amyloid beta-peptide and the intracellular accumulation of tau PubMed:22817713

Appears in Networks:
Annotations
Confidence
Medium
MeSH
Extracellular Space

a(MESH:"Neuropil Threads") association path(MESH:"Alzheimer Disease") View Subject | View Object

AD (Alzheimer’s disease) is a progressive neurodegenerative disorder characterized by the extracellular accumulation of senile plaques composed of Aβ (amyloid β-peptide) and the intracellular accumulation of the MAP (microtubuleassociated protein) tau into both non-filamentous and filamentous inclusions, such as NFTs (neurofibrillary tangles), NTs (neuropil threads) and NPs (neuritic plaques) [1,2] PubMed:22817713

Appears in Networks:
Annotations
Confidence
Medium
MeSH
Intracellular Space

path(MESH:"Plaque, Amyloid") positiveCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

AD (Alzheimer’s disease) is a progressive neurodegenerative disorder characterized by the extracellular accumulation of senile plaques composed of Aβ (amyloid β-peptide) and the intracellular accumulation of the MAP (microtubuleassociated protein) tau into both non-filamentous and filamentous inclusions, such as NFTs (neurofibrillary tangles), NTs (neuropil threads) and NPs (neuritic plaques) [1,2] PubMed:22817713

Appears in Networks:
Annotations
Confidence
Medium
MeSH
Extracellular Space

act(p(HGNC:ACE)) positiveCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

In addition, ACE expression also enhances Aβ clearance, and the levels and activity of ACE are elevated in AD brains (Barnes et al. 1991; Hemming and Selkoe 2005) PubMed:29626319

Appears in Networks:

p(HGNC:PICALM) negativeCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

And in AD, the decreasing expression of PICALM in brain endothelium reduces Aβ clearance (Zhao et al. 2015b) PubMed:29626319

Appears in Networks:
Annotations
MeSH
Alzheimer Disease

act(p(HGNC:SERPINF2)) negativeCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

However, the levels and activity of plasmin are reduced in AD brains (Ledesma et al. 2000) PubMed:29626319

Appears in Networks:

p(HGNC:MAPT) biomarkerFor path(MESH:"Alzheimer Disease") View Subject | View Object

Elevated CSF tau is a diagnostic biomarker in AD patients PubMed:29238289

Appears in Networks:
Annotations
MeSH
Cerebrospinal Fluid

p(HGNC:PICALM) negativeCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

Phosphatidylinositol binding clathrin assembly protein, PICALM (aka CALM) assembles adaptor protein-2 (AP-2) to clathrin, thus participating in clathrin-mediated endocytosis. We have previously reported that the level of full-length PICALM is decreased in AD brains; PICALM was co-localised with phosphorylated tau in NFTs and in granulovacuolar degenerations (GVDs) in the brains of AD patients and of individuals with Down syndrome but was not observed in amyloid plaques (Ando et al., 2013). PubMed:27260836

Appears in Networks:
Annotations
Disease Ontology (DO)
Alzheimer's disease
Disease Ontology (DO)
Down syndrome

act(a(CHEBI:acrolein)) positiveCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

We were prompted to carry out this study because Acr is mainly localized in the neurons [54], is found in association with NFTs and dystrophic neurites surrounding senile plaques [55], is highly toxic to neurons, is found elevated 2–5 fold in affected regions of AD brain. EC can sequester highly reactive and toxic byproducts of oxidation such as acrolein. PubMed:23531502

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a(CHEBI:homocysteine) biomarkerFor path(MESH:"Alzheimer Disease") View Subject | View Object

Receiver-operating characteristic curves and logistic regression analyses showed that combined assessment of DYRK1A, BDNF and homocysteine has a sensitivity of 0.952, a specificity of 0.889 and an accuracy of 0.933 in testing for AD. The blood levels of these markers provide a diagnosis assessment profile. Combined assessment of these three markers outperforms most of the previous markers and could become a useful substitute to the current panel of AD biomarkers. PubMed:28632203

Appears in Networks:
Annotations
Uberon
blood plasma
MeSH
Alzheimer Disease

a(CHEBI:memantine) decreases path(MESH:"Alzheimer Disease") View Subject | View Object

Primary cortical neurons exposed to the mitochondrial toxin NaN3 (0.1-3 mM) were submitted to oxidative stress with H2O2 (30-150 μM), to mimic conditions observed in neurodegenerative disorders. The effects of such treatment on a series of parameters useful in characterizing neuronal damage were investigated: (i) the basal release of glutamate, evaluated as (3)H-d-Aspartate efflux, was sharply, concentration-dependently, increased; (ii) the phosphorylation status of intracellular markers known to be involved in the neurodegenerative processes, in particular in Alzheimer disease: tau and GSK3β were increased, as well as the protein level of β-secretase (BACE1) and p35/25 evaluated by Western blotting, while (iii) the cell metabolic activity, measured with the MTT method, was reduced, in a concentration- and time-dependent manner. The latter effect, as well as tau hyperphosphorylation, was prevented both by a mixture of antioxidant drugs (100 μM ascorbic acid, 10 μM trolox, 100 μM glutathione) and by the anti-Alzheimer drug, memantine, 20 μM. PubMed:23722080

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a(HBP:"O-GlcNAcylation") negativeCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

This post-translational modification is likely an indicator of good health since its intracellular level correlates with the availability of extracellular glucose. From a more practical point of view, it has been shown that O-GlcNAcylation impairments contribute to the etiology of cardiovascular diseases, type-2 diabetes and Alzheimer's disease (AD), three illnesses common in occidental societies. PubMed:19732809

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a(HBP:Astrogliosis) biomarkerFor path(MESH:"Alzheimer Disease") View Subject | View Object

We show here that ITPKB protein level was increased 3-fold in the cerebral cortex of most patients with Alzheimer's disease compared with control subjects, and accumulated in dystrophic neurites associated to amyloid plaques. In mouse Neuro-2a neuroblastoma cells, Itpkb overexpression was associated with increased cell apoptosis and increased β-secretase 1 activity leading to overproduction of amyloid-β peptides. In this cellular model, an inhibitor of mitogen-activated kinase kinases 1/2 completely prevented overproduction of amyloid-β peptides. Transgenic overexpression of ITPKB in mouse forebrain neurons was not sufficient to induce amyloid plaque formation or tau hyperphosphorylation. However, in the 5X familial Alzheimer's disease mouse model, neuronal ITPKB overexpression significantly increased extracellular signal-regulated kinases 1/2 activation and β-secretase 1 activity, resulting in exacerbated Alzheimer's disease pathology as shown by increased astrogliosis, amyloid-β40 peptide production and tau hyperphosphorylation. PubMed:24401760

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bp(GO:"canonical glycolysis") negativeCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

Triosephosphate isomerase (TPI) is a key enzyme in cell metabolism that controls the glycolytic flow and energy production through the interconversion of dihydroxyacetone phosphate (DHAP) and D-glyceraldehyde 3-phosphate (G3P) (Richard, 1993). Notably, TPI is the only glycolytic enzyme whose functional deficiency is associated to neurodegeneration (Eber et al., 1991; Ovadi et al., 2004). In particular, inefficient glycolysis (Hoyer et al., 1988) and ATP depletion (Keil et al., 2004) are characteristic in Alzheimer’s disease brains. PubMed:19251756

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p(HGNC:SUMO1) positiveCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

The plasma level of SUMO1 was significantly increased in dementia patients, as compared to control groups. The levels of SUMO1 correlated to decreased Mini-Mental State Examination (r =-0.123, p = 0.029). These results suggest that elevated plasma SUMO1 levels may be associated with AD. PubMed:27716675

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composite(a(CHEBI:homocysteine), p(HGNC:BDNF), p(HGNC:DYRK1A)) biomarkerFor path(MESH:"Alzheimer Disease") View Subject | View Object

Receiver-operating characteristic curves and logistic regression analyses showed that combined assessment of DYRK1A, BDNF and homocysteine has a sensitivity of 0.952, a specificity of 0.889 and an accuracy of 0.933 in testing for AD. The blood levels of these markers provide a diagnosis assessment profile. Combined assessment of these three markers outperforms most of the previous markers and could become a useful substitute to the current panel of AD biomarkers. PubMed:28632203

Appears in Networks:
Annotations
Uberon
blood plasma
MeSH
Alzheimer Disease

p(HGNC:BDNF) biomarkerFor path(MESH:"Alzheimer Disease") View Subject | View Object

Receiver-operating characteristic curves and logistic regression analyses showed that combined assessment of DYRK1A, BDNF and homocysteine has a sensitivity of 0.952, a specificity of 0.889 and an accuracy of 0.933 in testing for AD. The blood levels of these markers provide a diagnosis assessment profile. Combined assessment of these three markers outperforms most of the previous markers and could become a useful substitute to the current panel of AD biomarkers. PubMed:28632203

Appears in Networks:
Annotations
Uberon
blood plasma
MeSH
Alzheimer Disease

p(HGNC:DYRK1A) biomarkerFor path(MESH:"Alzheimer Disease") View Subject | View Object

Receiver-operating characteristic curves and logistic regression analyses showed that combined assessment of DYRK1A, BDNF and homocysteine has a sensitivity of 0.952, a specificity of 0.889 and an accuracy of 0.933 in testing for AD. The blood levels of these markers provide a diagnosis assessment profile. Combined assessment of these three markers outperforms most of the previous markers and could become a useful substitute to the current panel of AD biomarkers. PubMed:28632203

Appears in Networks:
Annotations
Uberon
blood plasma
MeSH
Alzheimer Disease

p(HGNC:MAPT, pmod(Ac, Lys, 280)) positiveCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

We also tested for ac-tau 280 in early stage Alzheimer's disease (Braak stage 1). Histopathological examination using the ac tau 280 antibody was performed in three Alzheimer's cases and three CTE patients. Presence of ac-tau 280 was confirmed in all cases at early sites of disease manifestation. These findings suggest that tau acetylation may precede tau phosphorylation and could be the first PubMed:29276758

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Annotations
MeSH
Alzheimer Disease

p(HGNC:MAPT, pmod(Ac, Lys, 280)) positiveCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

Thus, K280 acetylation is a feature found in a variety of human 4R or 3R/4R tauopathies including AD, but not 3R-tauopathies such as PiD. PubMed:21427723

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g(DBSNP:rs10807287) association path(MESH:"Alzheimer Disease") View Subject | View Object

Haplotype analysis of the block formed by rs2651206, rs10807287, and rs7764257 showed that the combination of the three frequent alleles (CTA) was significantly (p = 0.02) overrepresented in the AD group (67%) compared to the control group (63%), and this result was still significant after multiple testing corrections with 10,000 permutations (p = 0.05). PubMed:20096481

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g(DBSNP:rs2651206) association path(MESH:"Alzheimer Disease") View Subject | View Object

Haplotype analysis of the block formed by rs2651206, rs10807287, and rs7764257 showed that the combination of the three frequent alleles (CTA) was significantly (p = 0.02) overrepresented in the AD group (67%) compared to the control group (63%), and this result was still significant after multiple testing corrections with 10,000 permutations (p = 0.05). PubMed:20096481

Appears in Networks:

g(DBSNP:rs2651206) positiveCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

Significant association with a reduced risk of LOAD (odds ratio/OR=0.69). rs2651206 polymorphism was strongly associated with LOAD (OR=0.72) (age, gender, and APOE adjusted). The TG haplotype, deriving from the two minor alleles, decreases risk of LOAD (OR=0.78, P=0.037). PubMed:21548880

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g(DBSNP:rs761059) positiveCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

The genotype distribution of a polymorphism in intron 7 (rs761059) differed between AD cases and controls, with an adjusted odds ratio (OR) of 1.45 (p=0.046, 95% CI: 1.01-2.08). One haplotype (ht2 CAGAG) was found in 14.0% of the AD patients and in 11.1% of the controls (p=0.04, OR=1.43. 95% CI; 1.01-2.01). Stratification by the ApoE gave no significant difference between the groups but when stratified by gender, two SNPs (rs8052688, rs8063) were significantly associated with the risk of MCI among women. PubMed:19765634

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g(DBSNP:rs7764257) association path(MESH:"Alzheimer Disease") View Subject | View Object

Haplotype analysis of the block formed by rs2651206, rs10807287, and rs7764257 showed that the combination of the three frequent alleles (CTA) was significantly (p = 0.02) overrepresented in the AD group (67%) compared to the control group (63%), and this result was still significant after multiple testing corrections with 10,000 permutations (p = 0.05). PubMed:20096481

Appears in Networks:

act(p(ECCODE:"2.3.2.13")) positiveCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

The number of neurons that are immunoreactive with an antibody directed at the epsilon-(gamma-glutamyl)lysine bond was significantly higher in AD cortex compared with age-matched controls and schizophrenics. PHF tau-directed antibodies AT8, MC-1 and PHF-1 co-localized with epsilon(gamma-glutamyl)lysine immunolabeling in AD NFT. Immunoaffinity purification and immunoblotting experiments demonstrated that PHF tau contains epsilon(gamma-glutamyl)lysine bonds in parietal and frontal cortex in AD. In control cases with NFT present in the entorhinal cortex and hippocampus, indicative of Braak and Braak stage II, epsilon(gamma-glutamyl)lysine bonds were present in PHF tau in parietal and frontal cortex, despite the lack of microscopically detectable NFT or senile plaques in these cortical regions. The presence of PHF tau with epsilon(gamma-glutamyl)lysine bonds in brain regions devoid of NFT in stage II (but regions, which would be expected to contain NFT in stage III) suggests that these bonds occur early in the formation of NFT. PubMed:11738469

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Annotations
Uberon
frontal cortex
Uberon
parietal cortex
Disease Ontology (DO)
Alzheimer's disease

act(p(ECCODE:"2.3.2.13")) positiveCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

Degenerating neurons from the AD hippocampus, compared to neurons from the normal aged hippocampus, exhibited increased immunoreactivity for TGase and demonstrated co-labeling for PHF1 and anti-TGase. Our results suggest that TGase may be associated with the neurofibrillary degeneration observed in AD, thereby implicating TGase as a potential factor in the pathogenesis of Alzheimer's disease. PubMed:8985134

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Annotations
Uberon
hippocampal formation
Disease Ontology (DO)
Alzheimer's disease

p(HBP:"CDK5R1 p25") positiveCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

To perform its function, Cdk5 must bind to the neuron-specific regulatory subunit protein p35, which is beneficial for neuronal development (Tsai et al. 1994; Chae et al. 1997). However, truncation of p35 and conversion to p25 (Patrick et al. 1999) is found in the forebrain of rats after focal cerebral ischemia and in AD patients, and these alterations are deleterious to the brain PubMed:26118667

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p(HBP:"Tau epitope, PHF1") biomarkerFor path(MESH:"Alzheimer Disease") View Subject | View Object

Finally, these data validate PHF-1 as an efficient marker for AD cytopathology following the progression of tau aggregation into NFT. PubMed:24033439

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p(HBP:"cis p-tau") negativeCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

Pin1 accelerates cis to trans conversion to prevent accumulation of pathogenic cis p-tau conformation in AD, providing the first structural evidence for how Pin1 protects against AD. PubMed:23157676

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p(HGNC:APP, frag("672_711")) biomarkerFor path(MESH:"Alzheimer Disease") View Subject | View Object

We show here that ITPKB protein level was increased 3-fold in the cerebral cortex of most patients with Alzheimer's disease compared with control subjects, and accumulated in dystrophic neurites associated to amyloid plaques. In mouse Neuro-2a neuroblastoma cells, Itpkb overexpression was associated with increased cell apoptosis and increased β-secretase 1 activity leading to overproduction of amyloid-β peptides. In this cellular model, an inhibitor of mitogen-activated kinase kinases 1/2 completely prevented overproduction of amyloid-β peptides. Transgenic overexpression of ITPKB in mouse forebrain neurons was not sufficient to induce amyloid plaque formation or tau hyperphosphorylation. However, in the 5X familial Alzheimer's disease mouse model, neuronal ITPKB overexpression significantly increased extracellular signal-regulated kinases 1/2 activation and β-secretase 1 activity, resulting in exacerbated Alzheimer's disease pathology as shown by increased astrogliosis, amyloid-β40 peptide production and tau hyperphosphorylation. PubMed:24401760

Appears in Networks:

p(HGNC:MAPT, pmod(HBP:hyperphosphorylation)) biomarkerFor path(MESH:"Alzheimer Disease") View Subject | View Object

We show here that ITPKB protein level was increased 3-fold in the cerebral cortex of most patients with Alzheimer's disease compared with control subjects, and accumulated in dystrophic neurites associated to amyloid plaques. In mouse Neuro-2a neuroblastoma cells, Itpkb overexpression was associated with increased cell apoptosis and increased β-secretase 1 activity leading to overproduction of amyloid-β peptides. In this cellular model, an inhibitor of mitogen-activated kinase kinases 1/2 completely prevented overproduction of amyloid-β peptides. Transgenic overexpression of ITPKB in mouse forebrain neurons was not sufficient to induce amyloid plaque formation or tau hyperphosphorylation. However, in the 5X familial Alzheimer's disease mouse model, neuronal ITPKB overexpression significantly increased extracellular signal-regulated kinases 1/2 activation and β-secretase 1 activity, resulting in exacerbated Alzheimer's disease pathology as shown by increased astrogliosis, amyloid-β40 peptide production and tau hyperphosphorylation. PubMed:24401760

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p(HGNC:MAPT, pmod(HBP:nitration, Tyr, 29)) positiveCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

Tau-nY29 detects soluble tau and paired helical filament tau from severely affected Alzheimer's brain but fails to recognize tau from normal aged brain. This observation suggests that nitration at Tyr29 is a disease-related event that may alter the intrinsic ability of tau to self-polymerize. In Alzheimer's brain, Tau-nY29 labels the fibrillar triad of tau lesions, including neurofibrillary tangles, neuritic plaques, and, to a lesser extent, neuropil threads. Intriguingly, although Tau-nY29 stains both the neuronal and glial tau pathology of Pick disease, it detects only the neuronal pathology in corticobasal degeneration and progressive supranuclear palsy without labeling the predominant glial pathology. PubMed:17050703

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Annotations
Disease Ontology (DO)
Alzheimer's disease

p(HGNC:MAPT, pmod(Ph, Thr, 231)) positiveCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

This sequence (Fig. 3G–N) is supported by Western blot analysis, phosphorylated Thr231 in three AD cases and their age-matched controls, suggesting that tau phosphorylation at Thr231 occurs before the formation of oligomers (Fig. 3O). PubMed:22253473

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MeSH
Alzheimer Disease

p(HGNC:MAPT, var("p.Asp13*")) positiveCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

While several N and C-terminally truncated Tau species are observed in AD brains, only a limited number of specific Tau cleavage sites, after residues Asp13, Asp25, Asn368, Glu391 and Asp421, have been identified so far in situ. The species generated by these cleavages are found in neurofibrillary tangles, and their occurrence is correlated with the severity of the disease. PubMed:25974414

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Annotations
Disease Ontology (DO)
Alzheimer's disease

p(HGNC:MAPT, var("p.Asp25*")) positiveCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

While several N and C-terminally truncated Tau species are observed in AD brains, only a limited number of specific Tau cleavage sites, after residues Asp13, Asp25, Asn368, Glu391 and Asp421, have been identified so far in situ. The species generated by these cleavages are found in neurofibrillary tangles, and their occurrence is correlated with the severity of the disease. PubMed:25974414

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Annotations
Disease Ontology (DO)
Alzheimer's disease

p(HGNC:MAPT, var("p.Asp368*")) positiveCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

While several N and C-terminally truncated Tau species are observed in AD brains, only a limited number of specific Tau cleavage sites, after residues Asp13, Asp25, Asn368, Glu391 and Asp421, have been identified so far in situ. The species generated by these cleavages are found in neurofibrillary tangles, and their occurrence is correlated with the severity of the disease. PubMed:25974414

Appears in Networks:
Annotations
Disease Ontology (DO)
Alzheimer's disease

p(HGNC:MAPT, var("p.Asp421*")) positiveCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

While several N and C-terminally truncated Tau species are observed in AD brains, only a limited number of specific Tau cleavage sites, after residues Asp13, Asp25, Asn368, Glu391 and Asp421, have been identified so far in situ. The species generated by these cleavages are found in neurofibrillary tangles, and their occurrence is correlated with the severity of the disease. PubMed:25974414

Appears in Networks:
Annotations
Disease Ontology (DO)
Alzheimer's disease

p(HGNC:MAPT, var("p.Glu391*")) positiveCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

While several N and C-terminally truncated Tau species are observed in AD brains, only a limited number of specific Tau cleavage sites, after residues Asp13, Asp25, Asn368, Glu391 and Asp421, have been identified so far in situ. The species generated by these cleavages are found in neurofibrillary tangles, and their occurrence is correlated with the severity of the disease. PubMed:25974414

Appears in Networks:
Annotations
Disease Ontology (DO)
Alzheimer's disease

p(HGNC:MARK4) positiveCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

In cells, a CagA peptide inhibited tau phosphorylation at Ser²6² mediated by MARK4 but not other MARK isoforms. A strong and significant elevation of MARK4 expression and MARK4-tau interactions in AD brains correlated with the Braak stages of the disease. PubMed:23666762

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act(p(HGNC:SIRT1)) negativeCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

SIRT1 activation or elevation ameliorates pathology and neurodegeneration in AD (Qin et al., 2006; Kim et al., 2007). Loss of SIRT1 induces impairment of learning and memory (Gao et al., 2010; Michán et al., 2010). PubMed:29540553

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p(HGNC:TGFB1) biomarkerFor path(MESH:"Alzheimer Disease") View Subject | View Object

Aβ 42 in the medium decreased in a GA dose-dependent manner (Fig. 3a). In contrast, GA significantly increased tau and its phosphorylated form, p-tauT181 (Fig. 3b,c) in the medium. In addition, VEGF (Fig. 3e) and TGF-β (Fig. 3f), which are also AD biomarkers, were increased when the concentration of GA added was greater than 0.7 mM. PubMed:26304819

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p(HGNC:VEGFA) biomarkerFor path(MESH:"Alzheimer Disease") View Subject | View Object

Aβ 42 in the medium decreased in a GA dose-dependent manner (Fig. 3a). In contrast, GA significantly increased tau and its phosphorylated form, p-tauT181 (Fig. 3b,c) in the medium. In addition, VEGF (Fig. 3e) and TGF-β (Fig. 3f), which are also AD biomarkers, were increased when the concentration of GA added was greater than 0.7 mM. PubMed:26304819

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p(INTERPRO:"Triosephosphate isomerase", pmod(NO, Tyr, 164)) positiveCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

Ab induced nitro-oxidative stress on human neuroblastoma cells, resulting in nitrotyrosination of TPI. Moreover, higher levels of nitro-TPI were also detected in extracts from hippocampus (Fig. 1F) and frontal cortex (Fig. 1G) obtained from Alzheimer’s disease brains, compared with healthy subjects. PubMed:19251756

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Annotations
Uberon
frontal cortex
Uberon
hippocampal formation
Disease Ontology (DO)
Alzheimer's disease

p(INTERPRO:"Triosephosphate isomerase", pmod(NO, Tyr, 208)) positiveCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

Ab induced nitro-oxidative stress on human neuroblastoma cells, resulting in nitrotyrosination of TPI. Moreover, higher levels of nitro-TPI were also detected in extracts from hippocampus (Fig. 1F) and frontal cortex (Fig. 1G) obtained from Alzheimer’s disease brains, compared with healthy subjects. PubMed:19251756

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Annotations
Uberon
frontal cortex
Uberon
hippocampal formation
Disease Ontology (DO)
Alzheimer's disease

p(MGI:Sirt1) negativeCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

Here we show that the protein deacetylase SIRT1 reduces tau acetylation in a mouse model of neurodegeneration. SIRT1 deficiency in the brain aggravates synapse loss and behavioral disinhibition, and SIRT1 overexpression ameliorates propagation of tau pathology. PubMed:29540553

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p(MGI:Sirt3) negativeCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

Sirt3 levels were reduced in the entorhinal cortex, the middle temporal gyrus, and the superior frontal gyrus of AD subjects compared to those of CN and was associated with poorer test scores of neuropsychological evaluation and the severity of tau pathology. PubMed:29540553

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Uberon
entorhinal cortex
Uberon
middle temporal gyrus
Uberon
superior frontal gyrus

bp(GO:aging) positiveCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

Aging, another risk factor of AD, has been found to activate the NLRP1 inflammasome and upregulate IL-18 and IL-1β levels in the hippocampus of aged mice (Mawhinney et al., 2011) PubMed:24561250

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Annotations
Confidence
Medium
MeSH
Hippocampus
NeuroMMSigDB
Interleukin signaling subgraph

complex(GO:"IPAF inflammasome complex") association path(MESH:"Alzheimer Disease") View Subject | View Object

In addition, NLRC4 and ASC levels are upregulated in the brains of AD patients (Liu and Chan, 2014), suggesting a possible role of the NLRC4 inflammasome in AD pathogenesis PubMed:24561250

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Annotations
Confidence
Medium
NeuroMMSigDB
Caspase subgraph

complex(GO:"NLRP3 inflammasome complex") association path(MESH:"Alzheimer Disease") View Subject | View Object

In support, a recent study in APP/PS1 mice confirms that the NLRP3 inflammasome contributes to the AD pathology (Heneka et al., 2013) PubMed:24561250

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Confidence
Medium

p(HGNC:PYCARD) positiveCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

In addition, NLRC4 and ASC levels are upregulated in the brains of AD patients (Liu and Chan, 2014), suggesting a possible role of the NLRC4 inflammasome in AD pathogenesis PubMed:24561250

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Annotations
Confidence
Medium
NeuroMMSigDB
Caspase subgraph

p(HGNC:NLRC4) positiveCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

In addition, NLRC4 and ASC levels are upregulated in the brains of AD patients (Liu and Chan, 2014), suggesting a possible role of the NLRC4 inflammasome in AD pathogenesis PubMed:24561250

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Annotations
Confidence
Medium
NeuroMMSigDB
Caspase subgraph

p(HGNC:IL18) positiveCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

Interleukins, in particular IL-1β and IL-18, are upregulated in AD brain, and the overexpression of IL-1β or IL-18 is critical for the onset of the inflammatory process (Rubio-Perez and Morillas-Ruiz, 2012), and both mediate the expression of a vast array of inflammatory genes (Weber et al., 2010) PubMed:24561250

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Annotations
Confidence
High
NeuroMMSigDB
Inflammatory response subgraph
NeuroMMSigDB
Interleukin signaling subgraph

p(HGNC:IL1B) positiveCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

Interleukins, in particular IL-1β and IL-18, are upregulated in AD brain, and the overexpression of IL-1β or IL-18 is critical for the onset of the inflammatory process (Rubio-Perez and Morillas-Ruiz, 2012), and both mediate the expression of a vast array of inflammatory genes (Weber et al., 2010) PubMed:24561250

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Annotations
Confidence
High
NeuroMMSigDB
Inflammatory response subgraph
NeuroMMSigDB
Interleukin signaling subgraph

path(MESH:"Trauma, Nervous System") increases path(MESH:"Alzheimer Disease") View Subject | View Object

Trauma, a risk factor for AD, increases inflammasome expression in rat neurons (de Rivero Vaccari et al., 2009; de Rivero Vaccari et al., 2008) PubMed:24561250

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Annotations
Confidence
Medium
MeSH
Neurons

complex(GO:"inflammasome complex") association path(MESH:"Alzheimer Disease") View Subject | View Object

They appear to be involved in several pathological processes activated by microbes including Alzheimer’s disease (AD). PubMed:27314526

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Confidence
High

p(HGNC:IL18) positiveCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

Increased levels of IL-1 beta and IL-18 have been detected in serum, cerebrospinal fluid, and brains of patients with AD and in other forms of dementia [42–46]. PubMed:27314526

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Annotations
Confidence
High
MeSH
Brain
MeSH
Cerebrospinal Fluid
MeSH
Serum
MeSH
Alzheimer Disease
NeuroMMSigDB
Interleukin signaling subgraph

p(HGNC:IL18) association path(MESH:"Alzheimer Disease") View Subject | View Object

Both these studies indicated an important role of IL-18 in AD. PubMed:27314526

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Annotations
Confidence
High
MeSH
Alzheimer Disease
NeuroMMSigDB
Interleukin signaling subgraph

p(HGNC:IL1B) positiveCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

Increased levels of IL-1 beta and IL-18 have been detected in serum, cerebrospinal fluid, and brains of patients with AD and in other forms of dementia [42–46]. PubMed:27314526

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Annotations
Confidence
High
MeSH
Brain
MeSH
Cerebrospinal Fluid
MeSH
Serum
MeSH
Alzheimer Disease
NeuroMMSigDB
Interleukin signaling subgraph

p(HGNC:P2RX7) positiveCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

P2X7 expressed by microglial cells will also activate the NLP3 inflammasome [30, 32] and the expression of P2X7 is likely to be increased in AD brains [35]. PubMed:27314526

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Annotations
Confidence
Medium
MeSH
Alzheimer Disease
NeuroMMSigDB
Caspase subgraph

p(HGNC:HSD17B10) positiveCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

Binding of Aβ to ABAD has been implicated in the development of AD, recent studies detected elevated ABAD levels in the regions of the hippocampus and cerebral cortex which are generally affected by AD pathology PubMed:30444369

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MeSH
Cerebral Cortex
MeSH
Hippocampus

complex(p(HGNC:APP), p(HGNC:HSD17B10)) increases path(MESH:"Alzheimer Disease") View Subject | View Object

Binding of Aβ to ABAD has been implicated in the development of AD, recent studies detected elevated ABAD levels in the regions of the hippocampus and cerebral cortex which are generally affected by AD pathology PubMed:30444369

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g(HBP:"APOE e4") increases path(MESH:"Alzheimer Disease") View Subject | View Object

Genetics have a role to play within AD; patients with a mutation in Amyloid Precursor Protein (APP), which results in overproduction of Aβ, will experience early onset AD. 36 Patients with a mutation in Apolipoprotein E4 (APOE4), which affects the clearance of Aβ, will experience late onset AD. PubMed:30444369

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g(HGNC:APP, var("?")) increases path(MESH:"Alzheimer Disease") View Subject | View Object

Genetics have a role to play within AD; patients with a mutation in Amyloid Precursor Protein (APP), which results in overproduction of Aβ, will experience early onset AD. 36 Patients with a mutation in Apolipoprotein E4 (APOE4), which affects the clearance of Aβ, will experience late onset AD. PubMed:30444369

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g(HGNC:PSEN1, var("?")) increases path(MESH:"Alzheimer Disease") View Subject | View Object

In addition, several other gene mutations have been discovered such as Presenilin-1 and Presenilin-2 mutations, which increase the risk for developing AD. 38 PubMed:30444369

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g(HGNC:PSEN2, var("?")) increases path(MESH:"Alzheimer Disease") View Subject | View Object

In addition, several other gene mutations have been discovered such as Presenilin-1 and Presenilin-2 mutations, which increase the risk for developing AD. 38 PubMed:30444369

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p(HGNC:CDK5) positiveCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

Inactivation of Prdx-2 is controlled by a kinase that has been shown to be elevated in AD, CDK5, 107, 108 which phosphorylates Thr 89 and results in deactivation of Prdx-2. PubMed:30444369

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Annotations
MeSH
Neurons

act(p(HGNC:PRDX2)) negativeCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

The first, peroxiredoxin-2 (Prdx-2), functions as an antioxidant and has been shown to be inactivated in AD. PubMed:30444369

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MeSH
Neurons

p(HGNC:PRDX2) positiveCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

In transgenic AD mice and the post-mortem human brain of AD patients, the expression of Prdx-2 is shown to be elevated, due to the attempted protection of neurons from Aβ-induced toxicity. PubMed:30444369

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MeSH
Neurons

p(HGNC:SH3GL2) positiveCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

The second ABAD-related protein, endophilin-1 (Ep-1), is a member of a family of proteins that are responsible for synaptic vesicle endocytosis, mitochondrial function, and receptor trafficking. 110 This family of proteins has been implicated in a number of neurodegenerative diseases, 111 including in AD where it is overexpressed PubMed:30444369

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MeSH
Neurons

a(HBP:"protein aggregates") positiveCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

Overexpression of the HSPB8-BAG3 complex also stimulates autophagy and facilitates the clearance of mutated aggregation-prone proteins, the accumulation of which characterizes many neurodegenerative disorders such as Alzheimer disease, Parkinson disease, and amyotrophic lateral sclerosis (Seidel et al., 2011). PubMed:22020111

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bp(MESH:"Oxidative Stress") positiveCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

A likely explanation for the increased expression of GLRX2 (glutaredoxin 2) and NQO1 (NAD(P)H dehydrogenase, quinone 1) in colon carcinoma and of GLRX (glutaredoxin), HMOX1 (heme oxygenase-1), NQO1, and SOD1 (superoxide dismutase 1) in Alzheimer is that it represents an adaptive attempt to partially compensate for the increased level of oxidative stress associated with these diseases. These antioxidant genes are also upregulated by Protandim, which would provide additional antioxidant protection beyond that achieved by the ROS-dependent induction of these enzymes in the diseased tissues. PubMed:22020111

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p(HGNC:GLRX) positiveCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

A likely explanation for the increased expression of GLRX2 (glutaredoxin 2) and NQO1 (NAD(P)H dehydrogenase, quinone 1) in colon carcinoma and of GLRX (glutaredoxin), HMOX1 (heme oxygenase-1), NQO1, and SOD1 (superoxide dismutase 1) in Alzheimer is that it represents an adaptive attempt to partially compensate for the increased level of oxidative stress associated with these diseases. These antioxidant genes are also upregulated by Protandim, which would provide additional antioxidant protection beyond that achieved by the ROS-dependent induction of these enzymes in the diseased tissues. PubMed:22020111

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p(HGNC:HMOX1) positiveCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

A likely explanation for the increased expression of GLRX2 (glutaredoxin 2) and NQO1 (NAD(P)H dehydrogenase, quinone 1) in colon carcinoma and of GLRX (glutaredoxin), HMOX1 (heme oxygenase-1), NQO1, and SOD1 (superoxide dismutase 1) in Alzheimer is that it represents an adaptive attempt to partially compensate for the increased level of oxidative stress associated with these diseases. These antioxidant genes are also upregulated by Protandim, which would provide additional antioxidant protection beyond that achieved by the ROS-dependent induction of these enzymes in the diseased tissues. PubMed:22020111

Appears in Networks:

p(HGNC:NQO1) positiveCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

A likely explanation for the increased expression of GLRX2 (glutaredoxin 2) and NQO1 (NAD(P)H dehydrogenase, quinone 1) in colon carcinoma and of GLRX (glutaredoxin), HMOX1 (heme oxygenase-1), NQO1, and SOD1 (superoxide dismutase 1) in Alzheimer is that it represents an adaptive attempt to partially compensate for the increased level of oxidative stress associated with these diseases. These antioxidant genes are also upregulated by Protandim, which would provide additional antioxidant protection beyond that achieved by the ROS-dependent induction of these enzymes in the diseased tissues. PubMed:22020111

Appears in Networks:

p(HGNC:SOD1) positiveCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

A likely explanation for the increased expression of GLRX2 (glutaredoxin 2) and NQO1 (NAD(P)H dehydrogenase, quinone 1) in colon carcinoma and of GLRX (glutaredoxin), HMOX1 (heme oxygenase-1), NQO1, and SOD1 (superoxide dismutase 1) in Alzheimer is that it represents an adaptive attempt to partially compensate for the increased level of oxidative stress associated with these diseases. These antioxidant genes are also upregulated by Protandim, which would provide additional antioxidant protection beyond that achieved by the ROS-dependent induction of these enzymes in the diseased tissues. PubMed:22020111

Appears in Networks:

a(MESH:"Receptors, N-Methyl-D-Aspartate") association path(MESH:"Alzheimer Disease") View Subject | View Object

PP2A enzymes can also associate with protein kinases that have been linked to AD, such as glycogen synthase kinase 3β (GSK3β) and cyclin-dependent kinase 5 (cdk5; Plattner et al.,2006), and neuronal receptors, e.g., the NMDA receptor (Chan and Sucher, 2001) and the metabotropic glutamate receptor 5 (Mao et al., 2005; Arif et al., 2014). PubMed:24653673

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act(complex(GO:"protein phosphatase type 2A complex")) negativeCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

There is a significant decrease in total PP2A activity measured in AD cortical and hippocampal brain homogenates (Gong et al.,1993; Gong et al.,1995; Sontag et al.,2004b). PubMed:24653673

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MeSH
Cerebral Cortex
MeSH
Hippocampus

complex(GO:"protein phosphatase type 2A complex") positiveCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

In contrast, “PP2A” expression levels are increased in AD astrocytes (Pei et al., 1997). PubMed:24653673

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MeSH
Astrocytes

act(complex(GO:"protein phosphatase type 2A complex")) negativeCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

Collectively, those studies point to a central role for PP2A dysfunction in AD pathogenesis PubMed:24653673

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p(HGNC:PPP2CA) negativeCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

Deficits in PP2A activity are in line with the reported down-regulation of PP2A catalytic C subunit at the gene (Loring et al.,2001), mRNA (Vogelsberg-Ragaglia et al.,2001) and protein (Sontag et al.,2004b) expression levels in AD. PubMed:24653673

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p(HGNC:PPP2CB) negativeCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

Deficits in PP2A activity are in line with the reported down-regulation of PP2A catalytic C subunit at the gene (Loring et al.,2001), mRNA (Vogelsberg-Ragaglia et al.,2001) and protein (Sontag et al.,2004b) expression levels in AD. PubMed:24653673

Appears in Networks:

p(HGNC:CDK5) association path(MESH:"Alzheimer Disease") View Subject | View Object

PP2A enzymes can also associate with protein kinases that have been linked to AD, such as glycogen synthase kinase 3β (GSK3β) and cyclin-dependent kinase 5 (cdk5; Plattner et al.,2006), and neuronal receptors, e.g., the NMDA receptor (Chan and Sucher, 2001) and the metabotropic glutamate receptor 5 (Mao et al., 2005; Arif et al., 2014). PubMed:24653673

Appears in Networks:

p(HGNC:GRM5) association path(MESH:"Alzheimer Disease") View Subject | View Object

PP2A enzymes can also associate with protein kinases that have been linked to AD, such as glycogen synthase kinase 3β (GSK3β) and cyclin-dependent kinase 5 (cdk5; Plattner et al.,2006), and neuronal receptors, e.g., the NMDA receptor (Chan and Sucher, 2001) and the metabotropic glutamate receptor 5 (Mao et al., 2005; Arif et al., 2014). PubMed:24653673

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p(HGNC:GSK3B) association path(MESH:"Alzheimer Disease") View Subject | View Object

PP2A enzymes can also associate with protein kinases that have been linked to AD, such as glycogen synthase kinase 3β (GSK3β) and cyclin-dependent kinase 5 (cdk5; Plattner et al.,2006), and neuronal receptors, e.g., the NMDA receptor (Chan and Sucher, 2001) and the metabotropic glutamate receptor 5 (Mao et al., 2005; Arif et al., 2014). PubMed:24653673

Appears in Networks:

p(HGNC:ANP32A) positiveCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

Up-regulation of I1 PP2A and I2 PP2A, and mislocalization and cleavage of I2 PP2A, could underlie the inactivation of PP2A in AD neocortical neurons (Tanimukai et al.,2005). PubMed:24653673

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MeSH
Neocortex
MeSH
Alzheimer Disease

complex(p(HGNC:FYN), p(HGNC:MAPT)) positiveCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

Conversely, decreased PP2A methylation and PP2A/Bα levels in AD will disrupt normal PP2A-tau interactions (Sontag et al., 2007), thereby preventing PP2A-mediated tau dephosphorylation while allowing for enhanced binding of Fyn kinase or other regulators to the tau proteins. PubMed:24653673

Appears in Networks:

complex(p(HGNC:MAPT), p(HGNC:PPP2CA), p(HGNC:PPP2R1A), p(INTERPRO:"Protein phosphatase 2A regulatory subunit PR55")) negativeCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

Conversely, decreased PP2A methylation and PP2A/Bα levels in AD will disrupt normal PP2A-tau interactions (Sontag et al., 2007), thereby preventing PP2A-mediated tau dephosphorylation while allowing for enhanced binding of Fyn kinase or other regulators to the tau proteins. PubMed:24653673

Appears in Networks:

p(INTERPRO:"Protein phosphatase 2A regulatory subunit PR55") negativeCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

More specifically, decreased expression levels of PP2A regulatory Bγ (or PPP2R2C) and B’ε (or PPP2R5E) subunit mRNAs in the hippocampus (Vogelsberg-Ragaglia et al.,2001), and cortical Bα subunit (Sontag et al.,2004b) have been reported in AD. PubMed:24653673

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MeSH
Cerebral Cortex

complex(p(HGNC:MAPT), p(HGNC:PPP2CB), p(HGNC:PPP2R1A), p(INTERPRO:"Protein phosphatase 2A regulatory subunit PR55")) negativeCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

Conversely, decreased PP2A methylation and PP2A/Bα levels in AD will disrupt normal PP2A-tau interactions (Sontag et al., 2007), thereby preventing PP2A-mediated tau dephosphorylation while allowing for enhanced binding of Fyn kinase or other regulators to the tau proteins. PubMed:24653673

Appears in Networks:

complex(p(HGNC:PPP2CA), p(HGNC:PPP2R1A), p(INTERPRO:"Protein phosphatase 2A regulatory subunit PR55")) negativeCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

Conversely, decreased PP2A methylation and PP2A/Bα levels in AD will disrupt normal PP2A-tau interactions (Sontag et al., 2007), thereby preventing PP2A-mediated tau dephosphorylation while allowing for enhanced binding of Fyn kinase or other regulators to the tau proteins. PubMed:24653673

Appears in Networks:

complex(p(HGNC:PPP2CA), p(HGNC:PPP2R1A), p(INTERPRO:"Protein phosphatase 2A regulatory subunit PR55")) negativeCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

The deregulation of PP2A methylation in AD is especially interesting, not only because it can lead to a loss of PP2A/Bα, a major tau regulator, but also because PP2A methylation state is intimately linked to the integrity of one-carbon metabolism, which regulates SAM supply (Reviewed in Fowler,2005). PubMed:24653673

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p(HGNC:PTPA) negativeCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

Decreased expression levels of PTPA in AD brain tissue may also lead to inactivation of PP2A by indirectly increasing levels of PP2A phosphorylated at the Tyr-307 site (Luo et al.,2013). PubMed:24653673

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MeSH
Alzheimer Disease

p(HGNC:SET) positiveCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

Up-regulation of I1 PP2A and I2 PP2A, and mislocalization and cleavage of I2 PP2A, could underlie the inactivation of PP2A in AD neocortical neurons (Tanimukai et al.,2005). PubMed:24653673

Appears in Networks:
Annotations
MeSH
Neocortex
MeSH
Alzheimer Disease

complex(p(HGNC:PPP2CB), p(HGNC:PPP2R1A), p(INTERPRO:"Protein phosphatase 2A regulatory subunit PR55")) negativeCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

Conversely, decreased PP2A methylation and PP2A/Bα levels in AD will disrupt normal PP2A-tau interactions (Sontag et al., 2007), thereby preventing PP2A-mediated tau dephosphorylation while allowing for enhanced binding of Fyn kinase or other regulators to the tau proteins. PubMed:24653673

Appears in Networks:

complex(p(HGNC:PPP2CB), p(HGNC:PPP2R1A), p(INTERPRO:"Protein phosphatase 2A regulatory subunit PR55")) negativeCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

The deregulation of PP2A methylation in AD is especially interesting, not only because it can lead to a loss of PP2A/Bα, a major tau regulator, but also because PP2A methylation state is intimately linked to the integrity of one-carbon metabolism, which regulates SAM supply (Reviewed in Fowler,2005). PubMed:24653673

Appears in Networks:

g(HGNC:PPP2CA) negativeCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

Deficits in PP2A activity are in line with the reported down-regulation of PP2A catalytic C subunit at the gene (Loring et al.,2001), mRNA (Vogelsberg-Ragaglia et al.,2001) and protein (Sontag et al.,2004b) expression levels in AD. PubMed:24653673

Appears in Networks:

g(HGNC:PPP2CB) negativeCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

Deficits in PP2A activity are in line with the reported down-regulation of PP2A catalytic C subunit at the gene (Loring et al.,2001), mRNA (Vogelsberg-Ragaglia et al.,2001) and protein (Sontag et al.,2004b) expression levels in AD. PubMed:24653673

Appears in Networks:

p(FPLX:PPP2, pmod(Me)) negativeCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

Significantly, down-regulation of LCMT1 protein expression parallels the deficits in PP2A methylation observed in AD (Sontag et al.,2004a). PubMed:24653673

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MeSH
Alzheimer Disease

p(FPLX:PPP2, pmod(Me)) negativeCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

Conversely, decreased PP2A methylation and PP2A/Bα levels in AD will disrupt normal PP2A-tau interactions (Sontag et al., 2007), thereby preventing PP2A-mediated tau dephosphorylation while allowing for enhanced binding of Fyn kinase or other regulators to the tau proteins. PubMed:24653673

Appears in Networks:

p(FPLX:PPP2, pmod(Me)) negativeCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

The deregulation of PP2A methylation in AD is especially interesting, not only because it can lead to a loss of PP2A/Bα, a major tau regulator, but also because PP2A methylation state is intimately linked to the integrity of one-carbon metabolism, which regulates SAM supply (Reviewed in Fowler,2005). PubMed:24653673

Appears in Networks:

p(HGNC:MAPT, pmod(Ph)) positiveCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

Conversely, decreased PP2A methylation and PP2A/Bα levels in AD will disrupt normal PP2A-tau interactions (Sontag et al., 2007), thereby preventing PP2A-mediated tau dephosphorylation while allowing for enhanced binding of Fyn kinase or other regulators to the tau proteins. PubMed:24653673

Appears in Networks:

p(HGNC:MAPT, pmod(Ph, Thr, 231)) positiveCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

This is potentially physiologically significant since phosphorylation of tau at Thr-231, a target site for ERK2, GSK3β, and cdk5, occurs early in AD and can further inhibit the ability of PP2A/Bα to dephosphorylate other major AD-tau phosphoepitopes (Landrieu et al.,2011). PubMed:24653673

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p(HGNC:SET, frag("?")) positiveCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

Up-regulation of I1 PP2A and I2 PP2A, and mislocalization and cleavage of I2 PP2A, could underlie the inactivation of PP2A in AD neocortical neurons (Tanimukai et al.,2005). PubMed:24653673

Appears in Networks:
Annotations
MeSH
Neocortex
MeSH
Alzheimer Disease

p(HGNC:SET, frag("?")) increases path(MESH:"Alzheimer Disease") View Subject | View Object

Moreover, expression of an I2 PP2A fragment can recapitulate AD-like pathology in rat brain (Wang et al.,2010). PubMed:24653673

Appears in Networks:

r(HGNC:PPP2CA) negativeCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

Deficits in PP2A activity are in line with the reported down-regulation of PP2A catalytic C subunit at the gene (Loring et al.,2001), mRNA (Vogelsberg-Ragaglia et al.,2001) and protein (Sontag et al.,2004b) expression levels in AD. PubMed:24653673

Appears in Networks:

r(HGNC:PPP2CB) negativeCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

Deficits in PP2A activity are in line with the reported down-regulation of PP2A catalytic C subunit at the gene (Loring et al.,2001), mRNA (Vogelsberg-Ragaglia et al.,2001) and protein (Sontag et al.,2004b) expression levels in AD. PubMed:24653673

Appears in Networks:

r(HGNC:PPP2R2C) negativeCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

More specifically, decreased expression levels of PP2A regulatory Bγ (or PPP2R2C) and B’ε (or PPP2R5E) subunit mRNAs in the hippocampus (Vogelsberg-Ragaglia et al.,2001), and cortical Bα subunit (Sontag et al.,2004b) have been reported in AD. PubMed:24653673

Appears in Networks:
Annotations
MeSH
Hippocampus

r(HGNC:PPP2R5E) negativeCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

More specifically, decreased expression levels of PP2A regulatory Bγ (or PPP2R2C) and B’ε (or PPP2R5E) subunit mRNAs in the hippocampus (Vogelsberg-Ragaglia et al.,2001), and cortical Bα subunit (Sontag et al.,2004b) have been reported in AD. PubMed:24653673

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MeSH
Hippocampus

a(HBP:"straight filaments") association path(MESH:"Alzheimer Disease") View Subject | View Object

For the sake of completeness, we also refer to tau- 3R transgenic mice that developed another type of pathology in the hippocampus, e.g., straight fila- ments formed in aged mice older than 18 mo (Ishi- hara, 2001b), which was proposed to be relevant for AD, given the age-dependence. PubMed:12428809

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bp(GO:"axonal transport") negativeCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

The following proposition has been recently reit- erated that axonal transport in AD could become disrupted by increased neuronal concentrations of tau protein PubMed:12428809

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p(HBP:"4R tau") positiveCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

Evidently, this argues for critical levels of protein tau-4R in the pathology of FTD and by exten- sion, in AD. PubMed:12428809

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p(HGNC:MAPT, pmod(Ph, Ser, 396), pmod(Ph, Ser, 404)) association path(MESH:"Alzheimer Disease") View Subject | View Object

More- over, the unbound tau protein was hyperphospho- rylated and especially at the AD-2 epitope, e.g., an epitope shown to contain serine 396 and serine 404. PubMed:12428809

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MeSH
Brain
MeSH
Spinal Cord

p(FPLX:PPP2C) negativeCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

Analyses of protein expression by using gel electrophore- sis and western blotting have shown not only a reduction of PP2A C expression levels but also a marked reduction of B55, thus indicating that PP2A impairment is the result of combined effects of different subunits [60]. PubMed:22299660

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p(HGNC:PPP2R2A) negativeCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

Analyses of protein expression by using gel electrophore- sis and western blotting have shown not only a reduction of PP2A C expression levels but also a marked reduction of B55, thus indicating that PP2A impairment is the result of combined effects of different subunits [60]. PubMed:22299660

Appears in Networks:

act(p(FPLX:PPP2)) negativeCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

Several observations showing reduced PP2A activity by 30% in the frontal cortex in AD [55], were followed by a number of studies of PP2A mRNA and proteins. PubMed:22299660

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MeSH
Frontal Lobe

act(p(FPLX:PPP2)) negativeCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

To sum up, PP2A activity is decreased in brain of AD, as revealed by using different approaches in different laboratories. PubMed:22299660

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MeSH
Brain

p(FPLX:PPP2C, pmod(Me, Leu, 309)) negativeCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

PP2A C methylation at Leu309 is reduced in AD and this seems to contribute to PP2A C dysfunction by impairing the assembly of the trimer [77, 78]. PubMed:22299660

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p(FPLX:PPP2C, pmod(Ph, Tyr, 307)) positiveCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

High levels of PP2A C phosphorylated at Tyr307 have been reported in the entorhinal cortex, hippocampus and frontal cortex in AD compared to controls [81]. PubMed:22299660

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MeSH
Entorhinal Cortex
MeSH
Frontal Lobe
MeSH
Hippocampus

p(HGNC:ANP32A) positiveCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

Complementing these findings, immu- nohistochemical and western blot studies have shown re- duced expression of PPMT [77], and up-regulation of the PP2A inhibitors I 1 and I 2 in AD cases [79, 80]. PubMed:22299660

Appears in Networks:

p(HGNC:ICMT) negativeCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

Complementing these findings, immu- nohistochemical and western blot studies have shown re- duced expression of PPMT [77], and up-regulation of the PP2A inhibitors I 1 and I 2 in AD cases [79, 80]. PubMed:22299660

Appears in Networks:

p(HGNC:MAPT, pmod(Ph, Ser, 189)) positiveCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

Similar findings have been observed in metabolically active rat brain slices, where a selective inhibition of PP2A with OA results in an aberrant phosphorylation of tau at the same residues seen in AD brains at serines (Ser) 198, 199, 202, 396, 404, 422 and 262 [11, 47, 48]. PubMed:22299660

Appears in Networks:

p(HGNC:MAPT, pmod(Ph, Ser, 199)) positiveCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

Similar findings have been observed in metabolically active rat brain slices, where a selective inhibition of PP2A with OA results in an aberrant phosphorylation of tau at the same residues seen in AD brains at serines (Ser) 198, 199, 202, 396, 404, 422 and 262 [11, 47, 48]. PubMed:22299660

Appears in Networks:

p(HGNC:MAPT, pmod(Ph, Ser, 202)) positiveCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

Similar findings have been observed in metabolically active rat brain slices, where a selective inhibition of PP2A with OA results in an aberrant phosphorylation of tau at the same residues seen in AD brains at serines (Ser) 198, 199, 202, 396, 404, 422 and 262 [11, 47, 48]. PubMed:22299660

Appears in Networks:

p(HGNC:MAPT, pmod(Ph, Ser, 262)) positiveCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

Similar findings have been observed in metabolically active rat brain slices, where a selective inhibition of PP2A with OA results in an aberrant phosphorylation of tau at the same residues seen in AD brains at serines (Ser) 198, 199, 202, 396, 404, 422 and 262 [11, 47, 48]. PubMed:22299660

Appears in Networks:

p(HGNC:MAPT, pmod(Ph, Ser, 396)) positiveCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

Similar findings have been observed in metabolically active rat brain slices, where a selective inhibition of PP2A with OA results in an aberrant phosphorylation of tau at the same residues seen in AD brains at serines (Ser) 198, 199, 202, 396, 404, 422 and 262 [11, 47, 48]. PubMed:22299660

Appears in Networks:

p(HGNC:MAPT, pmod(Ph, Ser, 404)) positiveCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

Similar findings have been observed in metabolically active rat brain slices, where a selective inhibition of PP2A with OA results in an aberrant phosphorylation of tau at the same residues seen in AD brains at serines (Ser) 198, 199, 202, 396, 404, 422 and 262 [11, 47, 48]. PubMed:22299660

Appears in Networks:

p(HGNC:MAPT, pmod(Ph, Ser, 422)) positiveCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

Similar findings have been observed in metabolically active rat brain slices, where a selective inhibition of PP2A with OA results in an aberrant phosphorylation of tau at the same residues seen in AD brains at serines (Ser) 198, 199, 202, 396, 404, 422 and 262 [11, 47, 48]. PubMed:22299660

Appears in Networks:

p(HGNC:SET) positiveCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

Complementing these findings, immu- nohistochemical and western blot studies have shown re- duced expression of PPMT [77], and up-regulation of the PP2A inhibitors I 1 and I 2 in AD cases [79, 80]. PubMed:22299660

Appears in Networks:

r(HGNC:PPP2CA) negativeCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

Decreased mRNA levels of PP2A C have been reported in the CA3 region of AD hippocampus by in situ RNA hybridisation [56]. Moreover, microarray RNA analysis carried out to compare the expression of more than 7,000 gene in the amygdala, cingulate cortex, striatum and cerebellum dis- closed down-regulation of the catalytic subunit PP2A C in AD [57]. This has been further corroborated by quantitative TaqMan PCR showing reduced PP2A C mRNA expression levels in the hippocampus, but not in the frontal cortex, in AD cases with disease progression Fig. (1). PubMed:22299660

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MeSH
CA3 Region, Hippocampal

r(HGNC:PPP2CB) negativeCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

Decreased mRNA levels of PP2A C have been reported in the CA3 region of AD hippocampus by in situ RNA hybridisation [56]. Moreover, microarray RNA analysis carried out to compare the expression of more than 7,000 gene in the amygdala, cingulate cortex, striatum and cerebellum dis- closed down-regulation of the catalytic subunit PP2A C in AD [57]. This has been further corroborated by quantitative TaqMan PCR showing reduced PP2A C mRNA expression levels in the hippocampus, but not in the frontal cortex, in AD cases with disease progression Fig. (1). PubMed:22299660

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MeSH
CA3 Region, Hippocampal

a(CHEBI:ceramide) positiveCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

Sphingolipids are also strongly implicated in AD pathology, with upregulated levels of ceramide, a key component in sphingolipid metabolism, detected in the early phase of AD [80]. PubMed:29758300

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a(GO:autolysosome) positiveCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

Other studies have also demonstrated the accumulation of autolysosomes in the AD brain and experimentally when lysosomal proteolysis is compromised via genetic knockdown of specific cathepsins or use of pharmacological inhibition of lysosomes [2,3,15] PubMed:29758300

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MeSH
Brain

a(HBP:"alpha-synuclein aggregates") association path(MESH:"Alzheimer Disease") View Subject | View Object

While AD is generally considered a disorder with two proteinopathies, other protein aggregates are also seen in AD, like α-synuclein PubMed:29758300

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a(HBP:"alpha-synuclein aggregates") positiveCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

First identified as a nonamyloid component of Aβ plaques in the AD brain, α-synuclein aggregates are detected in the majority of the brains of patients with AD [56,57]. PubMed:29758300

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MeSH
Brain

bp(GO:"lysosomal protein catabolic process") negativeCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

Such evidence of lysosomal proteolytic failure in AD brain further strengthens the concept that impaired macroautophagy in AD is a critical event PubMed:29758300

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MeSH
Brain

bp(GO:autophagy) negativeCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

Robust AV accumulation in dystrophic neurites from biopsy tissues from patients with AD implicate a compromised state of autophagic flux PubMed:29758300

Appears in Networks:

bp(GO:endocytosis) negativeCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

These results may be attributed to coincidental evidence of the involvement of Beclin 1 in VPS34-mediated trafficking pathways including macroautophagy and endocytosis [37], both of which are pronouncedly affected in AD pathology [38] PubMed:29758300

Appears in Networks:

bp(GO:macroautophagy) negativeCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

Since Nixon and colleagues first reported the pathological evidence of defective macroautophagy in EM images in the AD brain, similar observations have been made in cellular and animal models of AD [2,3,7,14] PubMed:29758300

Appears in Networks:

bp(GO:macroautophagy) negativeCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

Defects in macroautophagy in AD are supported by additional lines of evidence PubMed:29758300

Appears in Networks:

bp(GO:macroautophagy) negativeCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

Maintenance of neuronal macroautophagy can counteract AD pathology [22,23]. PubMed:29758300

Appears in Networks:
Annotations
MeSH
Neurons

bp(GO:macroautophagy) negativeCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

These results may be attributed to coincidental evidence of the involvement of Beclin 1 in VPS34-mediated trafficking pathways including macroautophagy and endocytosis [37], both of which are pronouncedly affected in AD pathology [38] PubMed:29758300

Appears in Networks:

p(HGNC:MAPT) association path(MESH:"Alzheimer Disease") View Subject | View Object

Dysregulation of tau proteins can produce a spectrum of neurodegenerative diseases or tauopathies characterized by dementia and tau deposition, including AD, frontotemporal dementia (FTD), Niemann- Pick disease, corticobasal degeneration (CBD), tangle-only dementia (TOD) and progressive supranuclear palsy (PSP). PubMed:29758300

Appears in Networks:

p(HGNC:SNCA) positiveCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

While misfolding of Aβ peptide and hyperphosphorylation of tau are recognized as pathogenic mechanisms of AD, accumulation of α-synuclein, which is recognized more as a risk factor for Parkinson’s disease (PD), also plays a pathological role in AD [29]. PubMed:29758300

Appears in Networks:

p(HGNC:SNCA) increases path(MESH:"Alzheimer Disease") View Subject | View Object

Recent clinical and immunohistochemistry studies demonstrate the contribution of α-synuclein in the development of AD pathology PubMed:29758300

Appears in Networks:

p(HGNC:SORL1) association path(MESH:"Alzheimer Disease") View Subject | View Object

One intriguing molecule that interacts with VPS35 is SORL1, a VPS10P-domain receptor protein that has been linked to autosomal dominant early-onset AD [116,117]. PubMed:29758300

Appears in Networks:

p(HGNC:TFEB) association path(MESH:"Alzheimer Disease") View Subject | View Object

Another modulator of A-LS implicated in AD pathology is transcription factor EB (TFEB), a master regulator of lysosome biogenesis PubMed:29758300

Appears in Networks:

g(HBP:"APOE e4") increases path(MESH:"Alzheimer Disease") View Subject | View Object

For instance, ApoE4–an important determinant of cholesterol metabolism and the strongest genetic risk factor for sporadic AD – regulates Aβ degradation [77]. PubMed:29758300

Appears in Networks:

p(HGNC:BECN1) negativeCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

For example, levels of Beclin 1, a key component of the class III type phosphoinositide 3-kinase/VPS34 complex essential to the pre-autophagosomal structure (PAS), has been suggested to be reduced in AD brains [16,17], with Rohn et al. demonstrating the cleavage of Beclin 1 by caspase-3 in the AD brain and colocalization of the cleaved product with NFTs [16]. PubMed:29758300

Appears in Networks:
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MeSH
Brain

p(HGNC:BIN1) positiveCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

Higher expression of BIN1 has been reported in AD brains, and suppression of BIN1 reduces tau toxicity, suggesting BIN1 involvement in tau pathology, as well [104]. PubMed:29758300

Appears in Networks:

p(HGNC:MAPT, pmod(HBP:hyperphosphorylation)) increases path(MESH:"Alzheimer Disease") View Subject | View Object

While misfolding of Aβ peptide and hyperphosphorylation of tau are recognized as pathogenic mechanisms of AD, accumulation of α-synuclein, which is recognized more as a risk factor for Parkinson’s disease (PD), also plays a pathological role in AD [29]. PubMed:29758300

Appears in Networks:

p(HGNC:MAPT, pmod(Ph)) increases path(MESH:"Alzheimer Disease") View Subject | View Object

Abnormal phosphorylation and truncation of tau are hallmarks of AD pathology and are targets of proteasome and autophagy pathways [27,44,45]. PubMed:29758300

Appears in Networks:

p(HGNC:MAPT, pmod(Ph, Ser, 262)) positiveCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

A recent study has demonstrated that activation of AMPKα1 enhances tau phosphorylation, while inhibition reduces tau phosphorylation at Ser-262, an epitope that is increased in early stages of AD, which promotes the autophagic degradation of tau [87] PubMed:29758300

Appears in Networks:

p(HGNC:PICALM, var("?")) association path(MESH:"Alzheimer Disease") View Subject | View Object

Multiple large-scale GWAS demonstrate that variants of PICALM (phosphatidylinositol-L-binding clathrin assembly protein involved in endocytosis) are significantly associated with AD [90,93,94]. PubMed:29758300

Appears in Networks:

p(HGNC:PSEN1, var("?")) association path(MESH:"Alzheimer Disease") View Subject | View Object

Furthermore, presenilin-1, the most common mutation associated with early-onset familial AD (FAD), plays an essential role in calcium homeostasis and maintaining acidic lysosomal pH, with FAD-associated mutations disrupting calcium-dependent vATPase function in lysosomes [7,18–20] PubMed:29758300

Appears in Networks:

p(HGNC:TREM2, var("?")) increases path(MESH:"Alzheimer Disease") View Subject | View Object

Variants of TREM2 have been found to increase the risk of developing AD by approximately three times [105,106], further validating it as a risk factor for AD. PubMed:29758300

Appears in Networks:

p(HGNC:VPS35, var("?")) association path(MESH:"Alzheimer Disease") View Subject | View Object

VPS35 mutations have been shown to disrupt macroautophagy [113] and mitochondrial function [114] and are associated with AD and PD [102,115]. PubMed:29758300

Appears in Networks:

p(MESH:"Amyloid beta-Peptides", pmod(HBP:misfolding)) increases path(MESH:"Alzheimer Disease") View Subject | View Object

While misfolding of Aβ peptide and hyperphosphorylation of tau are recognized as pathogenic mechanisms of AD, accumulation of α-synuclein, which is recognized more as a risk factor for Parkinson’s disease (PD), also plays a pathological role in AD [29]. PubMed:29758300

Appears in Networks:

path(HBP:"mitochondrial dysfunction") increases path(MESH:"Alzheimer Disease") View Subject | View Object

Mitochondria are instrumental in the regulation of energy metabolism, and impairment in mitochondrial function has been implicated in the pathogenesis of AD, leading to the mitochondrial cascade hypothesis of AD [121]. PubMed:29758300

Appears in Networks:

path(HBP:"mitochondrial dysfunction") increases path(MESH:"Alzheimer Disease") View Subject | View Object

Altogether, as with proteinopathy, accumulation of damaged or dysfunctional mitochondria is detrimental to the development of AD pathologies PubMed:29758300

Appears in Networks:

a(GO:autophagosome) positiveCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

The profuse and selective accumulation of AVs in neurons in AD reflects a defect in the clearance of AVs by lysosomes rather than an abnormally elevated induction of autophagy PubMed:22908190

Appears in Networks:
Annotations
MeSH
Neurons

a(GO:lysosome) positiveCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

A continuum of pathological changes of the lysosomal network unfolds in neurons as Alzheimer disease progresses, including dysregulation of endocytosis, increased lysosome biogenesis and, later, progressive failure of lysosomal clearance mechanisms (Fig. 6; Nixon et al. 2006). PubMed:22908190

Appears in Networks:

act(a(GO:lysosome)) negativeCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

The profuse and selective accumulation of AVs in neurons in AD reflects a defect in the clearance of AVs by lysosomes rather than an abnormally elevated induction of autophagy PubMed:22908190

Appears in Networks:
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MeSH
Neurons

act(a(GO:synapse)) negativeCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

The earliest symptoms of AD are believed to be due to synaptic dysfunction, and in this context, numerous studies have established a significant role of the UPS in the regulation of synaptic plasticity. PubMed:22908190

Appears in Networks:

act(a(GO:synapse)) negativeCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

Synaptic loss has long been documented in AD brain (Gonatas et al. 1967) and, as expected, is strongly correlated with the degree of cognitive impairment (Terry et al. 1991). PubMed:22908190

Appears in Networks:
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MeSH
Brain

a(HBP:"dystrophic neurite") positiveCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

AV accumulations are not specific to the degenerative phenomena of AD; however, in AD brain, the extensive numbers of dystrophic neurites (Masliah et al. 1993; Schmidt et al. 1994), their characteristic marked distension, and the fact that they are predominantly filled with AVs distinguish the pattern and magnitude of this pathology from that of other aging-related neurodegenerative diseases (Benzing et al. 1993). PubMed:22908190

Appears in Networks:

bp(GO:"axonal transport") negativeCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

AVs and lysosomes constitute more than 95% of the organelles in dystrophic neuritic swellings in AD and AD mouse models, implying a cargo-specific defect in axonal transport, rather than a global one. PubMed:22908190

Appears in Networks:
Annotations
MeSH
Alzheimer Disease

bp(GO:"lysosomal protein catabolic process") negativeCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

A continuum of pathological changes of the lysosomal network unfolds in neurons as Alzheimer disease progresses, including dysregulation of endocytosis, increased lysosome biogenesis and, later, progressive failure of lysosomal clearance mechanisms (Fig. 6; Nixon et al. 2006). PubMed:22908190

Appears in Networks:

bp(GO:autophagy) association path(MESH:"Alzheimer Disease") View Subject | View Object

Indeed, many recent studies suggest the involvement of autophagy in the pathogenesis of AD PubMed:22908190

Appears in Networks:

bp(GO:autophagy) association path(MESH:"Alzheimer Disease") View Subject | View Object

For example, immunocytochemistry showing the presence of K63- linked polyubiquitin in a fraction of the NFTs in AD cortex (Paine et al. 2009) suggests an active involvement of autophagy in the mechanism of AD. PubMed:22908190

Appears in Networks:
Annotations
MeSH
Alzheimer Disease

bp(GO:endocytosis) negativeCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

A continuum of pathological changes of the lysosomal network unfolds in neurons as Alzheimer disease progresses, including dysregulation of endocytosis, increased lysosome biogenesis and, later, progressive failure of lysosomal clearance mechanisms (Fig. 6; Nixon et al. 2006). PubMed:22908190

Appears in Networks:

bp(GO:endocytosis) negativeCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

Pathological Rab5 activation driving endocytic dysfunction in AD may negatively impact longterm potentiation (LTP) and long-term depression (LTD) aspects of synaptic plasticity closely associated with learning and memory (Kessels et al. 2009) PubMed:22908190

Appears in Networks:

p(HGNC:UBQLN1) association path(MESH:"Alzheimer Disease") View Subject | View Object

Next, ubiquilin-1 has been reported to be genetically linked to AD PubMed:22908190

Appears in Networks:

p(HGNC:APP, var("?")) positiveCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

App promoter polymorphisms that increase APP expression are also associated with early-onset AD (Athan et al. 2002). PubMed:22908190

Appears in Networks:

p(HGNC:APP, var("?")) positiveCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

These findings support a longstanding hypothesis that the App gene on the trisomic copy of human chromosome 21 (HSA21) in Down syndrome (DS) is principally responsible for the invariant early development of AD in DS individuals (Margallo-Lana et al. 2004). PubMed:22908190

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MeSH
Down Syndrome

g(HBP:"APOE e4") association path(MESH:"Alzheimer Disease") View Subject | View Object

Acceleration of endosome pathology is also seen in individuals who inherit the 14 allele of APOE, a key mediator of neuronal cholesterol transport and the major genetic risk factor for late-onset AD (Cataldo et al. 2000). PubMed:22908190

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MeSH
Neurons

p(HBP:"UBB+1") positiveCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

UBB+1 protein accumulates in brains affected by AD and other diseases such as Pick’s disease and Huntington’s disease (Fischer et al. 2003). PubMed:22908190

Appears in Networks:
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MeSH
Brain

p(HGNC:MAPT, pmod(Ub)) positiveCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

In AD, tau is ubiquitinated, in Parkinson’s disease and dementia with Lewy bodies, it is a-synuclein, and in ALS and FTLD-U, it is TDP-43 PubMed:22908190

Appears in Networks:

p(HGNC:PRKN) positiveCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

The E3 ligase Parkin, a protein implicated in Parkinson’s disease, creates an autophagy signal on mitochondria and also tags proteins elsewhere for proteasomal degradation (Yoshii et al. 2011). PubMed:22908190

Appears in Networks:

p(HGNC:PSEN1, var("?")) increases path(MESH:"Alzheimer Disease") View Subject | View Object

That presenilin 1 mutations, which are a cause of early-onset familial AD, impede lysosome proteolysis and accelerate neuritic dystrophy also supports a primary role for failure of proteolytic clearance (Lee et al. 2010). PubMed:22908190

Appears in Networks:

p(HGNC:RAB4A) positiveCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

Genes related to endocytosis, such as Rab5,Rab7, and Rab4, are among the earliest groups to showup-regulated transcription in AD(Ginsberg et al. 2010), and their corresponding proteins are abnormally recruited to endosomes, where they promote fusion and abnormal enlargement of early and late endosomes (Cataldo et al. 1997, 2008). PubMed:22908190

Appears in Networks:

p(HGNC:RAB5A) positiveCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

Genes related to endocytosis, such as Rab5,Rab7, and Rab4, are among the earliest groups to showup-regulated transcription in AD(Ginsberg et al. 2010), and their corresponding proteins are abnormally recruited to endosomes, where they promote fusion and abnormal enlargement of early and late endosomes (Cataldo et al. 1997, 2008). PubMed:22908190

Appears in Networks:

p(HGNC:RAB7A) positiveCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

Genes related to endocytosis, such as Rab5,Rab7, and Rab4, are among the earliest groups to showup-regulated transcription in AD(Ginsberg et al. 2010), and their corresponding proteins are abnormally recruited to endosomes, where they promote fusion and abnormal enlargement of early and late endosomes (Cataldo et al. 1997, 2008). PubMed:22908190

Appears in Networks:

p(HGNC:UBQLN1, var("?")) positiveCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

An intronic polymorphism involving alternative splicing of exon 8 in the ubiquilin 1 gene (UBQLN1), which is genetically located near a well-established linkage peak for AD on chromosome 9q22, has been associated with increased risk for late-onset AD (Bertram et al. 2005). PubMed:22908190

Appears in Networks:

p(HGNC:UCHL1) association path(MESH:"Alzheimer Disease") View Subject | View Object

Although UCH-L1 is genetically associated with Parkinson’s disease (i.e., it is the PARK5 gene; Belin and Westerlund 2008), it has also been implicated in the pathogenesis of AD PubMed:22908190

Appears in Networks:

a(GO:autophagosome) positiveCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

This suggestion originates from the observed accumulation of autophagic vacuoles in neurons from affected brain regions in a number of neurodegenerative diseases, including Alzheimer’s disease, Parkinson’s disease, Creutzfeldt- Jakob disease, and many of the polyglutamine diseases [21–24]. PubMed:18930136

Appears in Networks:
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MeSH
Neurons

a(GO:autophagosome) positiveCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

Alzheimer’s disease pathology features massive accumulation of autophagic vacuoles within large swellings along dystrophic and degenerating neurites in neocortical and hippocampal pyramidal neurons [21]. PubMed:18930136

Appears in Networks:
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MeSH
Hippocampus
MeSH
Neocortex
MeSH
Neurites
MeSH
Pyramidal Cells

p(HGNC:MAPT, pmod(HBP:hyperphosphorylation)) positiveCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

MAPT in AD and other tauopathies is hyperphosphorylated [29] and the hyperphosphorylation has been proposed to drive the missorting of MAPT. PubMed:30145931

Appears in Networks:

a(HBP:"Tau oligomers") positiveCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

Whereas control brain homogenate exhibited mainly Tau monomer, the AD brain contained a range of Tau assemblies ranging from n = 1 to n > 20 (Fig. 7, A and B). PubMed:25887395

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MeSH
Brain

a(HBP:"Tau aggregates") positiveCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

Tau from control brain purified in the monomer fraction (Figure 8A), while tau from AD brain distributed across multiple fractions, corresponding to monomer and larger assem- blies (Figure 8B). PubMed:29988016

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MeSH
Brain

p(HGNC:CHRNA7) positiveCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

AD brains show an upregulation of CHRNA7 (acr-14 homolog in humans) (84), where it may mediate the Ab-induced tau pathology (85). PubMed:29191965

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MeSH
Brain

p(HGNC:MAPT, pmod(Ph)) positiveCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

Phosphorylation is generally increased in AD and can be recognized by diagnostic antibodies against phosphoepitopes PubMed:29191965

Appears in Networks:

p(HGNC:MAPT, pmod(Ph)) positiveCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

For example, AD brain tau is;4-fold more phosphorylated than normal adult brain tau(93), but a high state of phosphorylation can also occur physiologically (e.g., in fetal brain or in hibernating animals (94). PubMed:29191965

Appears in Networks:

p(HGNC:MAPT, pmod(Ph, Ser, 202)) positiveCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

For example, both soluble and insoluble tau from transgenic worms generated by Kraemer and colleagues (66) was phosphorylated at most of the sites examined; however, the insoluble tau did not show reactivity at the AT8 and pS422 epitopes, which are pronounced in human AD tau. PubMed:29191965

Appears in Networks:

p(HGNC:MAPT, pmod(Ph, Ser, 422)) positiveCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

For example, both soluble and insoluble tau from transgenic worms generated by Kraemer and colleagues (66) was phosphorylated at most of the sites examined; however, the insoluble tau did not show reactivity at the AT8 and pS422 epitopes, which are pronounced in human AD tau. PubMed:29191965

Appears in Networks:

p(HGNC:MAPT, pmod(Ph, Thr, 205)) positiveCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

For example, both soluble and insoluble tau from transgenic worms generated by Kraemer and colleagues (66) was phosphorylated at most of the sites examined; however, the insoluble tau did not show reactivity at the AT8 and pS422 epitopes, which are pronounced in human AD tau. PubMed:29191965

Appears in Networks:

p(HGNC:MAPT, pmod(HBP:hyperphosphorylation)) positiveCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

In the pathological case of Alzheimer’s disease (AD) tau becomes hyperphosphorylated, detaches from the microtubules, misfolds, and mislocalizes to the somatodendritic compartment where it aggregates into neurofibrillary tangles. PubMed:25374103

Appears in Networks:
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MeSH
Alzheimer Disease

a(HBP:"Tau aggregates") positiveCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

Third, the phosphorylation of tau is often considered to enhance tau aggregation, as hyperphosphorylation and aggregation are both increased in AD PubMed:26631930

Appears in Networks:

a(HBP:"Tau oligomers") positiveCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

In an analogy to the evolution of concepts in the ‘amyloid cascade hypothesis’, which proposes that soluble oligomers — rather than insoluble aggregates of amyloid peptides — are the causative agents of neurodegeneration in AD, recent studies have suggested tau oligomers to be the toxic species, and indeed levels of SDS-stable tau oligomers are increased in AD and PSP brains. PubMed:26631930

Appears in Networks:
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MeSH
Brain

bp(GO:"neuron death") positiveCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

In brains of individuals with AD, neuron loss in the superior temporal sulcus region exceeds the number of NFTs more than sevenfold, implying that the majority of neurons probably die without having developed NFTs PubMed:26631930

Appears in Networks:

p(HBP:"3R tau") positiveCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

Tauopathies can be classified into three groups on the basis of the tau isoforms found in the aggregates: 4R tauopathies (including PSP, CBD and AGD), 3R tauopathies (for example, PiD) and 3R+4R tauopathies (for example, AD) PubMed:26631930

Appears in Networks:

p(HBP:"4R tau") positiveCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

Tauopathies can be classified into three groups on the basis of the tau isoforms found in the aggregates: 4R tauopathies (including PSP, CBD and AGD), 3R tauopathies (for example, PiD) and 3R+4R tauopathies (for example, AD) PubMed:26631930

Appears in Networks:

p(HGNC:MAPT) positiveCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

In AD and other tauopathies, the increase in dendritic tau levels is one of the first and most overt pathological abnormalities PubMed:26631930

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MeSH
Dendritic Spines

p(HGNC:MAPT, pmod(HBP:hyperphosphorylation)) positiveCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

Third, the phosphorylation of tau is often considered to enhance tau aggregation, as hyperphosphorylation and aggregation are both increased in AD PubMed:26631930

Appears in Networks:

p(HGNC:MAPT, frag("26_230")) positiveCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

For instance, a 20–22-kDa N‑terminal tau fragment (amino acids 26–230) was detected in an AD mouse model expressing a transgenic nerve growth factor (NGF)-specific antibody (AD11) and in the cerebrospinal fluid (CSF) of individuals with AD is neurotoxic in primary neurons PubMed:26631930

Appears in Networks:

p(HGNC:MAPT, pmod(Ac, Lys, 174)) positiveCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

Recently, tau acetylation at Lys174 was identified in human AD brains as well. PubMed:26631930

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MeSH
Brain

p(HGNC:MAPT, pmod(Ac, Lys, 280)) positiveCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

By contrast, acetylation of tau at Lys280 has been detected in AD and other tauopathies, including AGD, tangle-predominant senile dementia (TPSD), PiD, FTDP‑17 and PSP, and is pathological PubMed:26631930

Appears in Networks:

p(HGNC:MAPT, pmod(HBP:nitration, Tyr, 18)) positiveCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

The nitration of tau Tyr197 is found in the normal human brain and may have important physiological functions, whereas the nitration of Tyr18, Tyr29 and Tyr394 is detected only in AD or other tauopathies PubMed:26631930

Appears in Networks:

p(HGNC:MAPT, pmod(HBP:nitration, Tyr, 29)) positiveCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

The nitration of tau Tyr197 is found in the normal human brain and may have important physiological functions, whereas the nitration of Tyr18, Tyr29 and Tyr394 is detected only in AD or other tauopathies PubMed:26631930

Appears in Networks:

p(HGNC:MAPT, pmod(HBP:nitration, Tyr, 394)) positiveCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

The nitration of tau Tyr197 is found in the normal human brain and may have important physiological functions, whereas the nitration of Tyr18, Tyr29 and Tyr394 is detected only in AD or other tauopathies PubMed:26631930

Appears in Networks:

p(HGNC:MAPT, pmod(Me)) negativeCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

In human AD brains, PHF-tau is methylated at fewer sites than is tau from normal human brains PubMed:26631930

Appears in Networks:

p(HGNC:MAPT, pmod(NGlyco)) positiveCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

In human AD brains, but not in normal brains, tau is modified by N‑glycosylation, which is proposed to help to maintain and stabilize PHF structure PubMed:26631930

Appears in Networks:
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MeSH
Brain

p(HGNC:MAPT, pmod(Ph)) positiveCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

In AD, the phosphorylation of tau is increased further to approximately eight phosphates per molecule. PubMed:26631930

Appears in Networks:

p(HGNC:MAPT, pmod(Ph)) positiveCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

This view is supported by a recent study showing that tau in a normal mouse brain is phosphorylated at many sites that were previously found to be phosphorylated in tau from the brains of patients with AD. PubMed:26631930

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MeSH
Brain

p(HGNC:MAPT, pmod(Ph, Tyr, 18)) positiveCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

The phosphorylation of tau at Tyr394 and Tyr18 is present in PHFs in the brains of individuals with AD. PubMed:26631930

Appears in Networks:

act(p(HGNC:PPP2CA)) negativeCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

Among them, PP2A is the main phosphatase:it accounts for ~70% of the human brain tau phosphatase activity, and its activity is reduced in the AD brain (by ~20% and ~40% in the grey and white matter, respectively) PubMed:26631930

Appears in Networks:

r(HGNC:BACE1, loc(GO:cytoplasm)) positiveCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

For instance, measuring lncRNA BACE1 within the cytoplasm of the patients showed that its level in patients with Alzheimer’s was significantly higher than that in the control group PubMed:30663117

Appears in Networks:
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MeSH
Alzheimer Disease

r(HGNC:BACE1) increases path(MESH:"Alzheimer Disease") View Subject | View Object

BACE1‐AS can increase the expression of BACE1 mRNA by increasing its stability, which gives rise to AD PubMed:30663117

Appears in Networks:
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MeSH
Alzheimer Disease

g(HGNC:"MIR153-1") association path(MESH:"Alzheimer Disease") View Subject | View Object

Downregulation of miR‐153 increases the expression of APP and eventually, the production of β‐ameloid is promoted, increasing the risk of AD PubMed:30663117

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MeSH
Alzheimer Disease

g(HGNC:MIR384) association path(MESH:"Alzheimer Disease") View Subject | View Object

It was found that miR‐384, by binding to the 3′‐UTR sequence on BACE1 mRNA, could not only reduce expression in SH‐SY5Y cells but also attach to the 3′‐UTR sequence of the mRNA APP and reduce its expression, and this highlights the importance of miR‐384 in AD PubMed:30663117

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MeSH
Alzheimer Disease

g(HGNC:"MIR101-1") association path(MESH:"Alzheimer Disease") View Subject | View Object

Besides, by directly affecting APP, miR‐101 can cause its downregulation, which ultimately provides the basis for AD PubMed:30663117

Appears in Networks:
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MeSH
Alzheimer Disease

g(HGNC:"MIR101-1") decreases path(MESH:"Alzheimer Disease") View Subject | View Object

Given the important role of miR‐101 in preventing AD, miR‐101 reduction can play a role in AD development PubMed:30663117

Appears in Networks:
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MeSH
Alzheimer Disease

g(HGNC:"MIR9-1") association path(MESH:"Alzheimer Disease") View Subject | View Object

As regards, the MAPKK2 pathway, miR‐9 has been shown to inhibit tangles neurofibrillary by inhibiting this pathway and to play an important role in preventing AD. PubMed:30663117

Appears in Networks:
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MeSH
Alzheimer Disease

r(HGNC:"BACE1-AS") biomarkerFor path(MESH:"Alzheimer Disease") View Subject | View Object

BACE1‐AS is transcribed by opposite strand BACE1. Its upregulation in patients with Alzheimer’s can be used as a new biomarker for the diagnosis of this disease. PubMed:30663117

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MeSH
Alzheimer Disease

r(HGNC:"BACE1-AS") positiveCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

BACE1‐AS is transcribed by opposite strand BACE1. Its upregulation in patients with Alzheimer’s can be used as a new biomarker for the diagnosis of this disease. PubMed:30663117

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MeSH
Alzheimer Disease

p(HGNC:RELA) positiveCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

The results showed that the protein level of p65 sig- nificantly increased to 155.40¡13.39% in AD patient samples relative to control samples (p<0.05) (Fig. 1a). PubMed:21329555

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MeSH
Prefrontal Cortex

p(HGNC:BACE1) positiveCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

BACE1 mRNA levels were also markedly increased in the cortex of AD patients (126.40¡9.01% relative to controls, p<0.05) (Fig. 1b). PubMed:21329555

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Prefrontal Cortex

path(MESH:Inflammation) positiveCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

Inflammation is one of major pathological changes in AD brains and NF-kB signalling plays an important role in inflammation and oxidative stress (Tong et al. 2005). PubMed:21329555

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Brain

p(HGNC:IL6) association path(MESH:"Alzheimer Disease") View Subject | View Object

IL6 is another NF-κB – induced [256-260] pro-inflammatory cytokine up-regulated and integrally involved in the etio-pathogenesis of Alzheimer’s disease PubMed:28745240

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MeSH
Alzheimer Disease

p(HGNC:TNF) positiveCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

Another known target of NF-κB, TNFα [266, 267] is also up-regulated in the cortex [268], cerebrospinal fluid, and the serum of Alzheimer’s disease patients PubMed:28745240

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Alzheimer Disease

a(PUBCHEM:164676) decreases path(MESH:"Alzheimer Disease") View Subject | View Object

It inhibited the activation of iNOS, matrix metalloproteinase 2 (MMP2), and NF-Bp65 and consequently prevent AD in the brain [229–231]. PubMed:29179999

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Brain

a(PUBCHEM:442534) decreases path(MESH:"Alzheimer Disease") View Subject | View Object

It attenuated the development of AD by inhibiting glycogen synthase kinase 3 (GSK-3) and NF-B activation, and sup-pressing the NLRP3 inflammasome and cytokines such as TNF-and IL-1 [1]. PubMed:29179999

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p(FPLX:NFkappaB) positiveCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

Furthermore, A induced NF-B activity in glial and neuronal cells. NF-B is involved in inflammatory responses and is expressed in brains of AD patients [32]. PubMed:29179999

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Brain

a(CHEBI:"reactive oxygen species") positiveCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

Higher levels of ROS biomarkers are characteristic of AD patients in clinical and preclinical studies, resulting in the alteration of membrane proper- ties, such as fluidity, ion transport, enzyme activities, protein cross- linking, tau protein hyperphosphorylation, autophagic dysfunction and eventually neuron cell death [20]. PubMed:27288790

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a(CHEBI:pentosidine) positiveCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

Two AGEs, such as pentosidine and glyceraldehyde derived pyridinium (GLAP), both found increased in AD brains, were able to upregulate BACE1 through their binding with RAGE and consequent activation of NF-κB, providing a pathologic link between diabetes and AD [49]. PubMed:27288790

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Brain

a(HBP:GLAP) positiveCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

Two AGEs, such as pentosidine and glyceraldehyde derived pyridinium (GLAP), both found increased in AD brains, were able to upregulate BACE1 through their binding with RAGE and consequent activation of NF-κB, providing a pathologic link between diabetes and AD [49]. PubMed:27288790

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Brain

bp(GO:"MAPK cascade") positiveCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

Reports have indicated that MAPK signaling pathways are excessively activated in AD. PubMed:27288790

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bp(GO:"regulation of synaptic plasticity") negativeCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

In the nervous system, NF-κB has been proposed to serve important function by acting as a transcription regulator: it has roles in inflammation, neuronal survival, differentiation, apoptosis, neurite outgrowth, and synaptic plasticity [5], which are impaired in the progression of various neurodegenerative diseases especially in AD. PubMed:27288790

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MeSH
Nervous System

act(p(FPLX:NFkappaB)) positiveCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

NF-κB activation has also been detected in the brains of AD pa- tients. PubMed:27288790

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Brain

m(MIRBASE:"hsa-mir-146a") positiveCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

Elevated miRNA-146a in AD brain has been shown to also specifically target the interleukin-1 associated ki- nase-1 (IRAK-1) mRNAs, it is believed to contribute to altered innate immune responses and neuroinflammation in degenerating human brain cells and tissues in inflammatory neurodegenerative diseases including AD and in primary human brain cells stressed with ROS- generating metal sulfates [69]. PubMed:27288790

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Brain

p(HGNC:IL1B) positiveCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

TNF-α [27], IL-1β [28], IL-18 [29], CXCL10 [30] and TGF-β1 [31] are known to be elevated in the AD brain. PubMed:27288790

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Brain

m(MIRBASE:"hsa-mir-155") positiveCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

Specific up-regulation of miRNA-155 is observed in related immunopatho- logic conditions including MS and AD [70]. PubMed:27288790

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p(HGNC:CXCL10) positiveCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

TNF-α [27], IL-1β [28], IL-18 [29], CXCL10 [30] and TGF-β1 [31] are known to be elevated in the AD brain. PubMed:27288790

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MeSH
Brain

p(HGNC:IL18) positiveCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

TNF-α [27], IL-1β [28], IL-18 [29], CXCL10 [30] and TGF-β1 [31] are known to be elevated in the AD brain. PubMed:27288790

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MeSH
Brain

p(HGNC:PTGS2) positiveCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

In addition, COX-2, mainly regulated by NF-κB, is notably upregulated in the brains of AD patients, which may be associated with the formation of Aβ plaque [65]. PubMed:27288790

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Brain

p(HGNC:TGFB1) positiveCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

TNF-α [27], IL-1β [28], IL-18 [29], CXCL10 [30] and TGF-β1 [31] are known to be elevated in the AD brain. PubMed:27288790

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MeSH
Brain

p(HGNC:TNF) positiveCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

TNF-α [27], IL-1β [28], IL-18 [29], CXCL10 [30] and TGF-β1 [31] are known to be elevated in the AD brain. PubMed:27288790

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MeSH
Brain

path(MESH:Inflammation) positiveCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

Inflammation is a key pathological hall mark of AD [61,62], NF-κB is considered as a primary regulator of inflammatory processes [10]. PubMed:27288790

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a(MESH:"HLA-DR Antigens") positiveCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

Increased presence of activated glial cells presenting elevated NF-κB and HLA-DR expression are commonly observed around the Aβ plaques in postmortem AD tissue PubMed:25652642

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MeSH
Alzheimer Disease

act(complex(GO:"NF-kappaB complex")) positiveCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

These observations substantiate a direct role of neuronal NF–κB activation in the pathogenesis of AD PubMed:25652642

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MeSH
Neurons
MeSH
Alzheimer Disease

complex(GO:"NF-kappaB complex") positiveCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

Increased presence of activated glial cells presenting elevated NF-κB and HLA-DR expression are commonly observed around the Aβ plaques in postmortem AD tissue PubMed:25652642

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MeSH
Alzheimer Disease

complex(GO:"NF-kappaB complex") positiveCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

Increased presence of NF-κB mediated IL-1β, IL-6, and TNF-α cytokines have been reported in the affected tissues, serum and CSF of AD patients PubMed:25652642

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MeSH
Alzheimer Disease

p(HGNC:RELA) positiveCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

Comparison of the cellular distribution of NF-κB in the nucleus basalis of Meynert of AD and control patients showed that the proportion of large cholinergic neurons with elevated nuclear p65 was significantly increased in AD, suggesting an association between NF–κB functions and the process of cholinergic degeneration PubMed:25652642

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MeSH
Alzheimer Disease

complex(a(GO:"NF-kappaB complex"), p(HGNC:RELA)) positiveCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

. Consistent with the cellular studies, increased immunostaining for NF-κB-p65 has been observed in neurons and their processes in the hippocampal formation and entorhinal cortex in AD PubMed:25652642

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MeSH
Neurons
MeSH
Alzheimer Disease

m(HGNC:"MIR9-1") positiveCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

Upregulation of several NF-κB regulated miRNAs such as miRNA-9, miRNA-34a, miRNA-125b, miRNA-146a, miRNA-155 and miRNA-339 5p have been observed in stressed primary human neuronalglial cells and in postmortem AD brain tissues PubMed:25652642

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MeSH
Brain
MeSH
Neuroglia
MeSH
Alzheimer Disease

m(HGNC:MIR125B1) positiveCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

Upregulation of several NF-κB regulated miRNAs such as miRNA-9, miRNA-34a, miRNA-125b, miRNA-146a, miRNA-155 and miRNA-339 5p have been observed in stressed primary human neuronalglial cells and in postmortem AD brain tissues PubMed:25652642

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MeSH
Brain
MeSH
Neuroglia
MeSH
Alzheimer Disease

m(HGNC:MIR146A) positiveCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

Upregulation of several NF-κB regulated miRNAs such as miRNA-9, miRNA-34a, miRNA-125b, miRNA-146a, miRNA-155 and miRNA-339 5p have been observed in stressed primary human neuronalglial cells and in postmortem AD brain tissues PubMed:25652642

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MeSH
Brain
MeSH
Neuroglia
MeSH
Alzheimer Disease

m(HGNC:MIR155) positiveCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

Upregulation of several NF-κB regulated miRNAs such as miRNA-9, miRNA-34a, miRNA-125b, miRNA-146a, miRNA-155 and miRNA-339 5p have been observed in stressed primary human neuronalglial cells and in postmortem AD brain tissues PubMed:25652642

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MeSH
Brain
MeSH
Neuroglia
MeSH
Alzheimer Disease

m(HGNC:MIR339) positiveCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

Upregulation of several NF-κB regulated miRNAs such as miRNA-9, miRNA-34a, miRNA-125b, miRNA-146a, miRNA-155 and miRNA-339 5p have been observed in stressed primary human neuronalglial cells and in postmortem AD brain tissues PubMed:25652642

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MeSH
Brain
MeSH
Neuroglia
MeSH
Alzheimer Disease

m(HGNC:MIR34A) positiveCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

Upregulation of several NF-κB regulated miRNAs such as miRNA-9, miRNA-34a, miRNA-125b, miRNA-146a, miRNA-155 and miRNA-339 5p have been observed in stressed primary human neuronalglial cells and in postmortem AD brain tissues PubMed:25652642

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MeSH
Brain
MeSH
Neuroglia
MeSH
Alzheimer Disease

p(HGNC:IL1B) positiveCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

Increased presence of NF-κB mediated IL-1β, IL-6, and TNF-α cytokines have been reported in the affected tissues, serum and CSF of AD patients PubMed:25652642

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MeSH
Alzheimer Disease

p(HGNC:IL6) positiveCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

Increased presence of NF-κB mediated IL-1β, IL-6, and TNF-α cytokines have been reported in the affected tissues, serum and CSF of AD patients PubMed:25652642

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MeSH
Alzheimer Disease

p(HGNC:TNF) positiveCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

Increased presence of NF-κB mediated IL-1β, IL-6, and TNF-α cytokines have been reported in the affected tissues, serum and CSF of AD patients PubMed:25652642

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MeSH
Alzheimer Disease

p(HGNC:MAPT, pmod(HBP:hyperphosphorylation)) positiveCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

Moreover, pathological deposition of hyperphosphorylated MAP-tau (MAPT), which is the hallmark of several neurodegenerative disorders such as AD and frontotemporal dementia (FTD), has been described in elderly subjects with schizophrenia PubMed:30061532

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act(p(HGNC:MTOR)) increases path(MESH:"Alzheimer Disease") View Subject | View Object

On the other hand, some evidence indicates that suppressing mTOR activity ameliorates AD cognitive defects by decreasing Abeta and tau pathology PubMed:30061532

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p(HGNC:APOE) increases path(MESH:"Alzheimer Disease") View Subject | View Object

In the 3-month-old hippocampi (Figure 4B), we found significant sex-dependent changes for Adnp+/– gene regulation and NAP rescue in the following genes in male mice: (a) apolipoprotein E (Apoe), the lead gene for Alzheimer’s disease risk, which was shown before to be a major gene regulated by ADNP (10, 13); (b) Gm21949, which is suggested to play a role in calcium-mediated responses, action potential conduction in myelinated cells, and axonal outgrowth and guidance (6); (c) lipase A (Lipa), which is related to lipid metabolism and was previously shown to be regulated by the Adnp genotype in mice (3); (d) autism-associated neuroligin 2 (Nlgn2), a postsynaptic membrane cell adhesion protein that mediates the formation and maintenance of synapses between neurons (12); (e) paired box protein 6 (Pax6), a key regulator in glutamatergic neuronal differentiation (38) and cortical development (39), which was shown before by us to be regulated by ADNP (complete knockout of Adnp rendered Pax6 expression undetectable in the brain primordium, contrasting with increased expression in Adnp+/– embryos [ref. 1] and in subcortical brain domains of 2-month-old male Adnp+/– mice [ref. 3]); and (f) Wolframin endoplasmic reticulum transmembrane glycoprotein (Wfs1), which is associated with neurodegeneration and cellular calcium homeostasis regulation and was previously shown to be regulated by NAP (34). PubMed:30106381

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MeSH
Hippocampus
Gender
Male

Out-Edges 704

path(MESH:"Alzheimer Disease") positiveCorrelation a(HBP:HBP00018) View Subject | View Object

Extracellular deposition of amyloid-β aggregates, the main constituent of senile plaques, is considered to be a pathological hallmark of Alzheimer’s disease that contributes to neuronal dysfunction and behavioural changes PubMed:30046111

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Confidence
Medium
MeSH
Extracellular Space

path(MESH:"Alzheimer Disease") association act(a(MESH:"Lymphatic Vessels")) View Subject | View Object

Notably, although the fold change in significantly altered genes after lymphatic ablation and MWM was moderate (−1.79 < log2(fold change) < 1.69), functional enrichment analysis (Extended Data Fig. 5o, p) revealed changes in gene sets associated with neurodegenerative diseases, such as Huntington’s, Parkinson’s and Alzheimer’s disease (Extended Data Fig. 5o) PubMed:30046111

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Confidence
High
MeSH
Meninges

path(MESH:"Alzheimer Disease") positiveCorrelation a(CHEBI:"amyloid-beta") View Subject | View Object

Staining for amyloid-β in the brains of nine patients with Alzheimer’s disease and eight controls without Alzheimer’s disease (Extended Data Table 1) revealed, as expected, marked parenchymal deposition of amyloid-β in the brains of patients with Alzheimer’s disease, but not in the brains of the controls without Alzheimer’s disease (Extended Data Fig. 9l, m) PubMed:30046111

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Confidence
Medium
MeSH
Brain
MeSH
Parenchymal Tissue

path(MESH:"Alzheimer Disease") positiveCorrelation a(CHEBI:"amyloid-beta") View Subject | View Object

Notably, when compared to tissue from controls, all samples from patients with Alzheimer’s disease demonstrated striking vascular amyloid-β pathology in the cortical leptomeninges (Extended Data Fig. 9l, m) and amyloid-β deposition in the dura mater adjacent to the superior sagittal sinus (Fig. 3i, j) or further away from the sinus (Fig. 3k, l) PubMed:30046111

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Confidence
Medium
MeSH
Dura Mater
MeSH
Superior Sagittal Sinus

path(MESH:"Alzheimer Disease") positiveCorrelation a(CHEBI:"amyloid-beta") View Subject | View Object

These findings showed that prominent meningeal amyloid-β deposition observed in patients with Alzheimer’s disease is also observed in mouse models of Alzheimer’s disease after meningeal lymphatic vessel ablation PubMed:30046111

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Confidence
Medium
MeSH
Meninges
MeSH
Alzheimer Disease

path(MESH:"Alzheimer Disease") increases p(HGNC:BACE1) View Subject | View Object

We have examined the distribution of Asp 2 in AD hippocampus using a polyclonal antiserum raised to a peptide sequence derived from Asp 2 (see Experimental Methods).We see clear neuronal staining but there is no staining associated with astrocytes, microglia, or oligodendrocytes (Figs. 5a and 5b). PubMed:10656250

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MeSH
Hippocampus

path(MESH:"Alzheimer Disease") increases complex(p(HGNC:ESR1), p(HGNC:MAPT)) View Subject | View Object

Moreover, more ERα was found in the tau-5 immunoprecipitates from AD brain than control brain (p < 0.05) (Fig. 5B,C), demonstrating increased interaction between tau and ERα in the AD brain which is likely the mechanism that underlies increased sequestration of ERα by the PHFs in NFTs. PubMed:26837465

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Confidence
High
MeSH
Cerebral Cortex
MeSH
Hippocampus

path(MESH:"Alzheimer Disease") isA path(MESH:"Neurodegenerative Diseases") View Subject | View Object

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path(MESH:"Alzheimer Disease") decreases bp(GO:cognition) View Subject | View Object

AD belongs to a large group of neurodegenerative diseases (NDs) characterized by cognitive impairment and progressive synaptic damage accompanied by neuronal loss. PubMed:29196815

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Confidence
High

path(MESH:"Alzheimer Disease") increases bp(GO:"positive regulation of neuron apoptotic process") View Subject | View Object

AD belongs to a large group of neurodegenerative diseases (NDs) characterized by cognitive impairment and progressive synaptic damage accompanied by neuronal loss. PubMed:29196815

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Confidence
High

path(MESH:"Alzheimer Disease") positiveCorrelation a(CHEBI:"amyloid-beta") View Subject | View Object

The histopathological changes in the brain include the presence of extracellular amyloid plaques consisted of various peptide variants of amyloid β (Aβ) and accumulation of intracellular neurofibrillary tangles (NFTs) composed mainly of phosphorylated Tau proteins (pTau), localized predominantly in neurons (reviewed by Serrano-Pozo et al. 2011). PubMed:29196815

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Confidence
Medium

path(MESH:"Alzheimer Disease") positiveCorrelation a(CHEBI:"amyloid-beta") View Subject | View Object

Amyloid hypothesis is supported by the fact that progressive Aβ deposition is observed in early, preclinical stages of AD and, finally, in all AD patients. PubMed:29196815

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Confidence
High

path(MESH:"Alzheimer Disease") positiveCorrelation path(MESH:"Plaque, Amyloid") View Subject | View Object

The histopathological changes in the brain include the presence of extracellular amyloid plaques consisted of various peptide variants of amyloid β (Aβ) and accumulation of intracellular neurofibrillary tangles (NFTs) composed mainly of phosphorylated Tau proteins (pTau), localized predominantly in neurons (reviewed by Serrano-Pozo et al. 2011). PubMed:29196815

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Confidence
Medium

path(MESH:"Alzheimer Disease") positiveCorrelation a(MESH:"Amyloid beta-Peptides") View Subject | View Object

The histopathological changes in the brain include the presence of extracellular amyloid plaques consisted of various peptide variants of amyloid β (Aβ) and accumulation of intracellular neurofibrillary tangles (NFTs) composed mainly of phosphorylated Tau proteins (pTau), localized predominantly in neurons (reviewed by Serrano-Pozo et al. 2011). PubMed:29196815

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Confidence
Medium

path(MESH:"Alzheimer Disease") positiveCorrelation a(GO:"neurofibrillary tangle") View Subject | View Object

The histopathological changes in the brain include the presence of extracellular amyloid plaques consisted of various peptide variants of amyloid β (Aβ) and accumulation of intracellular neurofibrillary tangles (NFTs) composed mainly of phosphorylated Tau proteins (pTau), localized predominantly in neurons (reviewed by Serrano-Pozo et al. 2011). PubMed:29196815

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Confidence
Medium

path(MESH:"Alzheimer Disease") positiveCorrelation a(HBP:HBP00074) View Subject | View Object

In very early stages of AD pathology, before the appearance of amyloid plaques, oligomers assemble perisomatically, rather than intracellularly, surrounding individual diffuse neurons. PubMed:29196815

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MeSH
Extracellular Space
Cell Ontology (CL)
neuron
Confidence
High

path(MESH:"Alzheimer Disease") positiveCorrelation a(HBP:HBP00074) View Subject | View Object

They revealed increases in AβOs and soluble TNF-R plasma levels that accurately differentiated mild AD patients from control subjects and to some extent from amnestic mild cognitive impairment (aMCI) patients. PubMed:29196815

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MeSH
Extracellular Space
Cell Ontology (CL)
neuron
Confidence
High
MeSH
Plasma

path(MESH:"Alzheimer Disease") negativeCorrelation a(CHEBI:"amyloid-beta polypeptide 42") View Subject | View Object

Despite enhanced Aβ42 accumulation in AD brain (Lewczuk et al. 2003), concentrations of monomeric Aβ42 in the CSF of AD patients are decreased PubMed:29196815

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MeSH
Extracellular Space
Cell Ontology (CL)
neuron
Confidence
High
MeSH
Hippocampus

path(MESH:"Alzheimer Disease") positiveCorrelation a(HBP:HBP00076) View Subject | View Object

Using a novel misfolded protein assay for the detection of soluble oligomers composed of Aβx-40 and Aβx-42 peptides, Gao and co-workers demonstrated also increased levels of oligomeric Aβ40 in CSF, which may be a potential biomarker for the diagnosis of AD (Gao et al. 2010). PubMed:29196815

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MeSH
Extracellular Space
Cell Ontology (CL)
neuron
Confidence
High
MeSH
Cerebrospinal Fluid

path(MESH:"Alzheimer Disease") positiveCorrelation p(HGNC:NGFR) View Subject | View Object

They revealed increases in AβOs and soluble TNF-R plasma levels that accurately differentiated mild AD patients from control subjects and to some extent from amnestic mild cognitive impairment (aMCI) patients. PubMed:29196815

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MeSH
Extracellular Space
Cell Ontology (CL)
neuron
Confidence
High
MeSH
Plasma

path(MESH:"Alzheimer Disease") positiveCorrelation r(HBP:HBP00064) View Subject | View Object

There are reports showing that the protein and mRNA levels of KPI-containing APP isoforms are elevated in AD brain and associated with increased Ab deposition [9]; and prolonged activation of extrasynaptic NMDA receptor in neurons can shift APP expression from APP695 to KPI-containing APP isoforms, accompanied with increased production of Ab [10] PubMed:21214928

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Confidence
Medium

path(MESH:"Alzheimer Disease") positiveCorrelation p(HBP:HBP00065) View Subject | View Object

There are reports showing that the protein and mRNA levels of KPI-containing APP isoforms are elevated in AD brain and associated with increased Ab deposition [9]; and prolonged activation of extrasynaptic NMDA receptor in neurons can shift APP expression from APP695 to KPI-containing APP isoforms, accompanied with increased production of Ab [10] PubMed:21214928

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Confidence
Medium

path(MESH:"Alzheimer Disease") negativeCorrelation p(HGNC:ADAM10) View Subject | View Object

A dramatically reduced ADAM10 protein level in the platelets of sporadic AD patients was also found to correlate with the significantly decreased sAPPalpha levels found in their platlets and cerebrospinal fluid [55] and the reduced alpha-secretase activity in the temporal cortex homogenates of AD patients [56] PubMed:21214928

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Confidence
Medium
MeSH
Blood Platelets

path(MESH:"Alzheimer Disease") negativeCorrelation act(p(HGNC:ADAM10)) View Subject | View Object

A dramatically reduced ADAM10 protein level in the platelets of sporadic AD patients was also found to correlate with the significantly decreased sAPPalpha levels found in their platlets and cerebrospinal fluid [55] and the reduced alpha-secretase activity in the temporal cortex homogenates of AD patients [56] PubMed:21214928

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Confidence
Medium
MeSH
Temporal Lobe

path(MESH:"Alzheimer Disease") negativeCorrelation a(HBP:HBP00067) View Subject | View Object

A dramatically reduced ADAM10 protein level in the platelets of sporadic AD patients was also found to correlate with the significantly decreased sAPPalpha levels found in their platlets and cerebrospinal fluid [55] and the reduced alpha-secretase activity in the temporal cortex homogenates of AD patients [56] PubMed:21214928

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Confidence
Medium
MeSH
Blood Platelets
MeSH
Cerebrospinal Fluid

path(MESH:"Alzheimer Disease") association a(MESH:"Amyloid beta-Peptides") View Subject | View Object

Plaques consisting of beta-amyloid (Abeta) peptide (Selkoe 1998), neurofibrillary tangles consisting largely of hyperphosphorylated microtubule-associated tau protein (Buee et al. 2000; Gendron and Petrucelli 2009) and neuron loss in the hippocampus and cortex regions are the major pathological hallmarks of Alzheimer’s disease. PubMed:22122372

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Confidence
High

path(MESH:"Alzheimer Disease") association bp(GO:"neurofibrillary tangle assembly") View Subject | View Object

Plaques consisting of beta-amyloid (Abeta) peptide (Selkoe 1998), neurofibrillary tangles consisting largely of hyperphosphorylated microtubule-associated tau protein (Buee et al. 2000; Gendron and Petrucelli 2009) and neuron loss in the hippocampus and cortex regions are the major pathological hallmarks of Alzheimer’s disease. PubMed:22122372

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Confidence
High

path(MESH:"Alzheimer Disease") association bp(GO:"neuron death") View Subject | View Object

Plaques consisting of beta-amyloid (Abeta) peptide (Selkoe 1998), neurofibrillary tangles consisting largely of hyperphosphorylated microtubule-associated tau protein (Buee et al. 2000; Gendron and Petrucelli 2009) and neuron loss in the hippocampus and cortex regions are the major pathological hallmarks of Alzheimer’s disease. PubMed:22122372

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Confidence
High
MeSH
Cerebral Cortex
MeSH
Hippocampus

path(MESH:"Alzheimer Disease") positiveCorrelation a(HBP:HBP00064) View Subject | View Object

The levels of APP isoforms with a KPI domain seem to be elevated in patients with AD (Menendez- Gonzalez et al. 2005) and a splicing shift in neurons from APP695 to KPI-containing APP isoforms, along with increased Abeta generation, is observed when the NMDA receptor is activated (Bordji et al. 2010) PubMed:22122372

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Confidence
Medium
MeSH
Neurons

path(MESH:"Alzheimer Disease") positiveCorrelation a(HBP:HBP00065) View Subject | View Object

The levels of APP isoforms with a KPI domain seem to be elevated in patients with AD (Menendez- Gonzalez et al. 2005) and a splicing shift in neurons from APP695 to KPI-containing APP isoforms, along with increased Abeta generation, is observed when the NMDA receptor is activated (Bordji et al. 2010) PubMed:22122372

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Confidence
Medium
MeSH
Neurons

path(MESH:"Alzheimer Disease") negativeCorrelation p(HBP:"alpha-4 beta-2 nAChR") View Subject | View Object

As will be returned to below, it is also the first nAChR subtype to exhibit measurable decline in expression in the aged mammalian brain and especially in neurodegenerative disorders such as AD (236, 374). PubMed:19126755

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Text Location
Review

path(MESH:"Alzheimer Disease") negativeCorrelation p(HBP:"alpha-4 beta-2 nAChR") View Subject | View Object

In particular, the association of the alpha7 nAChR gene with a sensory gating deficit that is similar to attention deficits in patients with schizophrenia (157), and the degree of alpha4beta2 nAChR loss and altered alpha7 expresson correlate well with the magnitude of progressive cognitive decline in mild-to-moderate AD patients (46). PubMed:19126755

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Text Location
Review

path(MESH:"Alzheimer Disease") negativeCorrelation act(p(HGNCGENEFAMILY:"Cholinergic receptors nicotinic subunits")) View Subject | View Object

Reduced nAChR function/expression in the brain has been associated with the pathophysiology of catastrophic disorders, including AD and schizophrenia (discussed in later sections, and see Refs. 277, 432). PubMed:19126755

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path(MESH:"Alzheimer Disease") negativeCorrelation p(HGNCGENEFAMILY:"Cholinergic receptors nicotinic subunits") View Subject | View Object

However, loss of brain nAChRs precedes that of muscarinic receptors during normal aging, and it is often much more extensive in human brains afflicted with AD relative to age-matched controls (236, 308, 373, 374, 416, 519). In fact, alpha4 nAChR expression can decrease by >80% in the AD brain (306, 374). PubMed:19126755

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path(MESH:"Alzheimer Disease") positiveCorrelation p(HGNCGENEFAMILY:"Cholinergic receptors nicotinic subunits") View Subject | View Object

It is noteworthy that nAChR expression by astrocytes in brains afflicted with AD is increased (463, 518), and astrocytes in general have been reported to be more plentiful in the hippocampus of some rat strains with age (35, 284). PubMed:19126755

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Astrocytes
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path(MESH:"Alzheimer Disease") negativeCorrelation p(HGNC:CHRNA7) View Subject | View Object

In particular, the association of the alpha7 nAChR gene with a sensory gating deficit that is similar to attention deficits in patients with schizophrenia (157), and the degree of alpha4beta2 nAChR loss and altered alpha7 expresson correlate well with the magnitude of progressive cognitive decline in mild-to-moderate AD patients (46). PubMed:19126755

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path(MESH:"Alzheimer Disease") negativeCorrelation bp(GO:cognition) View Subject | View Object

Chronic alpha7 nAChR inhibition in the hippocampus by elevated levels of KYNA can contribute to auditory gating deficits, which appear to be associated with the development of schizophrenia (156). It is also feasible that KYNAinduced inhibition of alpha7 nAChRs contributes to the cognitive impairment observed in patients with AD and schizophrenia (273). PubMed:19126755

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Hippocampus
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Review

path(MESH:"Alzheimer Disease") positiveCorrelation path(MESH:Dementia) View Subject | View Object

AD is the most common form of dementia in the elderly population. The histopathology of this disease is well known to have at least four components: 1) loss of cholinergic neurotransmission, 2) deposition of extracellular Abeta peptides into plaques, 3) hyperphosphorylation of the tau protein that leads to excessive formation of neurofibrillar tangles, and 4) increased local inflammation. PubMed:19126755

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path(MESH:"Alzheimer Disease") negativeCorrelation bp(GO:"synaptic transmission, cholinergic") View Subject | View Object

AD is the most common form of dementia in the elderly population. The histopathology of this disease is well known to have at least four components: 1) loss of cholinergic neurotransmission, 2) deposition of extracellular Abeta peptides into plaques, 3) hyperphosphorylation of the tau protein that leads to excessive formation of neurofibrillar tangles, and 4) increased local inflammation. PubMed:19126755

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path(MESH:"Alzheimer Disease") positiveCorrelation path(MESH:"Plaque, Amyloid") View Subject | View Object

AD is the most common form of dementia in the elderly population. The histopathology of this disease is well known to have at least four components: 1) loss of cholinergic neurotransmission, 2) deposition of extracellular Abeta peptides into plaques, 3) hyperphosphorylation of the tau protein that leads to excessive formation of neurofibrillar tangles, and 4) increased local inflammation. PubMed:19126755

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path(MESH:"Alzheimer Disease") positiveCorrelation path(MESH:"Neurofibrillary Tangles") View Subject | View Object

AD is the most common form of dementia in the elderly population. The histopathology of this disease is well known to have at least four components: 1) loss of cholinergic neurotransmission, 2) deposition of extracellular Abeta peptides into plaques, 3) hyperphosphorylation of the tau protein that leads to excessive formation of neurofibrillar tangles, and 4) increased local inflammation. PubMed:19126755

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path(MESH:"Alzheimer Disease") positiveCorrelation path(MESH:"Neurogenic Inflammation") View Subject | View Object

AD is the most common form of dementia in the elderly population. The histopathology of this disease is well known to have at least four components: 1) loss of cholinergic neurotransmission, 2) deposition of extracellular Abeta peptides into plaques, 3) hyperphosphorylation of the tau protein that leads to excessive formation of neurofibrillar tangles, and 4) increased local inflammation. PubMed:19126755

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path(MESH:"Alzheimer Disease") negativeCorrelation p(HGNC:CHRNA4) View Subject | View Object

However, loss of brain nAChRs precedes that of muscarinic receptors during normal aging, and it is often much more extensive in human brains afflicted with AD relative to age-matched controls (236, 308, 373, 374, 416, 519). In fact, alpha4 nAChR expression can decrease by >80% in the AD brain (306, 374). PubMed:19126755

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path(MESH:"Alzheimer Disease") association path(MESH:Dementia) View Subject | View Object

Alzheimer’s disease (AD) is the most common form of dementia in elderly persons. It is a neurodegenerative disease marked by decline in memory and cognitive performance, including deterioration of language as well as defects in visual and motor coordination, and eventual death (for review, see Cummings, 2004). PubMed:19293145

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path(MESH:"Alzheimer Disease") decreases bp(GO:memory) View Subject | View Object

Alzheimer’s disease (AD) is the most common form of dementia in elderly persons. It is a neurodegenerative disease marked by decline in memory and cognitive performance, including deterioration of language as well as defects in visual and motor coordination, and eventual death (for review, see Cummings, 2004). PubMed:19293145

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path(MESH:"Alzheimer Disease") decreases bp(GO:cognition) View Subject | View Object

Alzheimer’s disease (AD) is the most common form of dementia in elderly persons. It is a neurodegenerative disease marked by decline in memory and cognitive performance, including deterioration of language as well as defects in visual and motor coordination, and eventual death (for review, see Cummings, 2004). PubMed:19293145

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path(MESH:"Alzheimer Disease") decreases path(MESH:"Psychomotor Performance") View Subject | View Object

Alzheimer’s disease (AD) is the most common form of dementia in elderly persons. It is a neurodegenerative disease marked by decline in memory and cognitive performance, including deterioration of language as well as defects in visual and motor coordination, and eventual death (for review, see Cummings, 2004). PubMed:19293145

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path(MESH:"Alzheimer Disease") association path(MESH:Death) View Subject | View Object

Alzheimer’s disease (AD) is the most common form of dementia in elderly persons. It is a neurodegenerative disease marked by decline in memory and cognitive performance, including deterioration of language as well as defects in visual and motor coordination, and eventual death (for review, see Cummings, 2004). PubMed:19293145

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path(MESH:"Alzheimer Disease") increases bp(GO:"neuron death") View Subject | View Object

AD also involves loss of neurons, beginning in the entorhinal cortex and later spreading to the neocortex (Braak et al., 2006); early in the disease, nicotinic acetylcholine receptors (nAChRs) are lost (Kadir et al., 2006). PubMed:19293145

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MeSH
Entorhinal Cortex
MeSH
Neocortex

path(MESH:"Alzheimer Disease") decreases p(HGNCGENEFAMILY:"Cholinergic receptors nicotinic subunits") View Subject | View Object

AD also involves loss of neurons, beginning in the entorhinal cortex and later spreading to the neocortex (Braak et al., 2006); early in the disease, nicotinic acetylcholine receptors (nAChRs) are lost (Kadir et al., 2006). PubMed:19293145

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path(MESH:"Alzheimer Disease") decreases act(p(HGNCGENEFAMILY:"Cholinergic receptors nicotinic subunits")) View Subject | View Object

Several lines of evidence point to a link between brain nAChRs and the development of AD. Biochemical analysis of brains of patients with AD reveals deficits in nAChRs, an increase in butyrylcholinesterase, reduction in ACh, and attenuated activity of cholinergic synthetic [choline acetyltransferase (ChAT)] and inactivating (AChE) enzymes (Bartus et al., 1982; Francis et al., 1999).Butyrylcholinesterase and AChE help terminate ACh signaling by hydrolyzing the transmitter, thereby inactivating it. PubMed:19293145

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path(MESH:"Alzheimer Disease") association act(p(HGNCGENEFAMILY:"Cholinergic receptors nicotinic subunits")) View Subject | View Object

Thus, although other mechanisms are also involved in the development of AD, there is abundant evidence that defects in cholinergic synaptic transmission and, in particular, nAChR-mediated signaling plays a major role in the disease and are hence the subject of attempts to generate new routes to therapy. PubMed:19293145

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path(MESH:"Alzheimer Disease") decreases p(HGNCGENEFAMILY:"Cholinergic receptors nicotinic subunits") View Subject | View Object

It is clear that AD involves loss of cholinergic neurons in the brain as well as an overall reduction in nAChRs, and it seems that different subunits are differentially up- or down-regulated in AD in different brain regions and different cell types. PubMed:19293145

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MeSH
Brain

path(MESH:"Alzheimer Disease") increases p(HGNCGENEFAMILY:"Cholinergic receptors nicotinic subunits") View Subject | View Object

Thus, predominantly alpha4 and alpha7 subunits, and to a lesser extent alpha3 subunits, are lost in AD, although there are tissue-specific differences to this pattern, such as the upregulation of nAChRs on astrocytes. PubMed:19293145

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MeSH
Astrocytes

path(MESH:"Alzheimer Disease") positiveCorrelation a(MESH:"Neurofibrillary Tangles") View Subject | View Object

AD is characterized pathologically by the occurrence of intracellular neurofibrillary tangles rich in tau protein and extracellular plaques containing amyloid peptides (Price et al., 1991). PubMed:19293145

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path(MESH:"Alzheimer Disease") positiveCorrelation path(MESH:"Plaque, Amyloid") View Subject | View Object

AD is characterized pathologically by the occurrence of intracellular neurofibrillary tangles rich in tau protein and extracellular plaques containing amyloid peptides (Price et al., 1991). PubMed:19293145

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path(MESH:"Alzheimer Disease") association path(MESH:"Plaque, Amyloid") View Subject | View Object

APP and APP/presenilin-1 (PS-1) mice do not show neurodegeneration (Irizarry et al., 1997) and yet show several features of AD, including accumulation of plaques and defects in learning (Hsiao et al., 1996), suggesting that many features of AD are not the result of neuronal loss. These animals nonetheless have swollen cholinergic nerve terminals at 12 months, suggesting defective nerve sprouting (Hernandez et al., 2001). PubMed:19293145

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path(MESH:"Alzheimer Disease") association a(HBP:"amyloid-beta aggregates") View Subject | View Object

It is generally agreed that the beta-amyloid peptide (Abeta) plays an important role in the development of AD. The brains of patients with AD contain deposits of Abeta, and Abeta is toxic to cultured neurons (Kihara et al., 1997a; Yao et al., 2005). In addition, mice transgenically overexpressing Abeta or with mutations that enhance Abeta aggregation show many of the symptoms of AD (Hsiao et al., 1996; van Groen et al., 2006). PubMed:19293145

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MeSH
Brain

path(MESH:"Alzheimer Disease") association a(CHEBI:"amyloid-beta polypeptide 42") View Subject | View Object

An increasing ratio of the full-length, 1–42 peptide to the 1–40 form is associated with disease (Kumar-Singh et al., 2006), and mutations underlying familial forms of AD either increase this ratio or increase the amount of Abeta secreted. PubMed:19293145

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path(MESH:"Alzheimer Disease") association sec(a(CHEBI:"amyloid-beta")) View Subject | View Object

An increasing ratio of the full-length, 1–42 peptide to the 1–40 form is associated with disease (Kumar-Singh et al., 2006), and mutations underlying familial forms of AD either increase this ratio or increase the amount of Abeta secreted. PubMed:19293145

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path(MESH:"Alzheimer Disease") association a(CHEBI:"amyloid-beta") View Subject | View Object

APP and APP/presenilin-1 (PS-1) mice do not show neurodegeneration (Irizarry et al., 1997) and yet show several features of AD, including accumulation of plaques and defects in learning (Hsiao et al., 1996), suggesting that many features of AD are not the result of neuronal loss. These animals nonetheless have swollen cholinergic nerve terminals at 12 months, suggesting defective nerve sprouting (Hernandez et al., 2001). PubMed:19293145

Appears in Networks:

path(MESH:"Alzheimer Disease") increases p(HGNC:BCHE) View Subject | View Object

Several lines of evidence point to a link between brain nAChRs and the development of AD. Biochemical analysis of brains of patients with AD reveals deficits in nAChRs, an increase in butyrylcholinesterase, reduction in ACh, and attenuated activity of cholinergic synthetic [choline acetyltransferase (ChAT)] and inactivating (AChE) enzymes (Bartus et al., 1982; Francis et al., 1999).Butyrylcholinesterase and AChE help terminate ACh signaling by hydrolyzing the transmitter, thereby inactivating it. PubMed:19293145

Appears in Networks:

path(MESH:"Alzheimer Disease") decreases a(CHEBI:acetylcholine) View Subject | View Object

Several lines of evidence point to a link between brain nAChRs and the development of AD. Biochemical analysis of brains of patients with AD reveals deficits in nAChRs, an increase in butyrylcholinesterase, reduction in ACh, and attenuated activity of cholinergic synthetic [choline acetyltransferase (ChAT)] and inactivating (AChE) enzymes (Bartus et al., 1982; Francis et al., 1999).Butyrylcholinesterase and AChE help terminate ACh signaling by hydrolyzing the transmitter, thereby inactivating it. PubMed:19293145

Appears in Networks:

path(MESH:"Alzheimer Disease") decreases act(p(HGNC:CHAT)) View Subject | View Object

Several lines of evidence point to a link between brain nAChRs and the development of AD. Biochemical analysis of brains of patients with AD reveals deficits in nAChRs, an increase in butyrylcholinesterase, reduction in ACh, and attenuated activity of cholinergic synthetic [choline acetyltransferase (ChAT)] and inactivating (AChE) enzymes (Bartus et al., 1982; Francis et al., 1999).Butyrylcholinesterase and AChE help terminate ACh signaling by hydrolyzing the transmitter, thereby inactivating it. PubMed:19293145

Appears in Networks:

path(MESH:"Alzheimer Disease") decreases act(p(HGNC:CHAT)) View Subject | View Object

AD involves loss of cholinergic cells not only in the cortex but also in subcortical nuclei. Up to 50% loss of neurons and of ChAT activity has been reported at autopsy in the locus ceruleus of brains from patients with AD compared with brains from subjects without AD, whereas no change was observed for adrenergic brainstem nuclei (Strong et al., 1991). PubMed:19293145

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MeSH
Basal Ganglia

path(MESH:"Alzheimer Disease") decreases act(a(MESH:"Cholinesterase Inhibitors")) View Subject | View Object

Several lines of evidence point to a link between brain nAChRs and the development of AD. Biochemical analysis of brains of patients with AD reveals deficits in nAChRs, an increase in butyrylcholinesterase, reduction in ACh, and attenuated activity of cholinergic synthetic [choline acetyltransferase (ChAT)] and inactivating (AChE) enzymes (Bartus et al., 1982; Francis et al., 1999).Butyrylcholinesterase and AChE help terminate ACh signaling by hydrolyzing the transmitter, thereby inactivating it. PubMed:19293145

Appears in Networks:

path(MESH:"Alzheimer Disease") association g(HGNC:CHAT) View Subject | View Object

Genetic association studies investigating single nucleotide polymorphisms point to roles for cholinergic signaling components such as the synthetic enzyme ChAT, the inactivating enzyme AChE, and alpha4beta2 nAChRs in AD (Cook et al., 2004, 2005; Vasto et al., 2006). The most vulnerable neurons in AD seem to be those expressing high levels of nAChRs, particularly those containing the alpha7 subunit (D’Andrea and Nagele, 2006), and the numbers of nAChRs as well as some of their associated proteins change in AD (Martin-Ruiz et al., 1999; Gotti et al., 2006; Sabbagh et al., 2006). PubMed:19293145

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path(MESH:"Alzheimer Disease") association g(HGNC:ACHE) View Subject | View Object

Genetic association studies investigating single nucleotide polymorphisms point to roles for cholinergic signaling components such as the synthetic enzyme ChAT, the inactivating enzyme AChE, and alpha4beta2 nAChRs in AD (Cook et al., 2004, 2005; Vasto et al., 2006). The most vulnerable neurons in AD seem to be those expressing high levels of nAChRs, particularly those containing the alpha7 subunit (D’Andrea and Nagele, 2006), and the numbers of nAChRs as well as some of their associated proteins change in AD (Martin-Ruiz et al., 1999; Gotti et al., 2006; Sabbagh et al., 2006). PubMed:19293145

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path(MESH:"Alzheimer Disease") association a(HBP:"alpha-4 beta-2 nAChR") View Subject | View Object

Genetic association studies investigating single nucleotide polymorphisms point to roles for cholinergic signaling components such as the synthetic enzyme ChAT, the inactivating enzyme AChE, and alpha4beta2 nAChRs in AD (Cook et al., 2004, 2005; Vasto et al., 2006). The most vulnerable neurons in AD seem to be those expressing high levels of nAChRs, particularly those containing the alpha7 subunit (D’Andrea and Nagele, 2006), and the numbers of nAChRs as well as some of their associated proteins change in AD (Martin-Ruiz et al., 1999; Gotti et al., 2006; Sabbagh et al., 2006). PubMed:19293145

Appears in Networks:

path(MESH:"Alzheimer Disease") association p(HGNC:CHRNA7) View Subject | View Object

Genetic association studies investigating single nucleotide polymorphisms point to roles for cholinergic signaling components such as the synthetic enzyme ChAT, the inactivating enzyme AChE, and alpha4beta2 nAChRs in AD (Cook et al., 2004, 2005; Vasto et al., 2006). The most vulnerable neurons in AD seem to be those expressing high levels of nAChRs, particularly those containing the alpha7 subunit (D’Andrea and Nagele, 2006), and the numbers of nAChRs as well as some of their associated proteins change in AD (Martin-Ruiz et al., 1999; Gotti et al., 2006; Sabbagh et al., 2006). PubMed:19293145

Appears in Networks:

path(MESH:"Alzheimer Disease") decreases p(HGNC:CHRNA7) View Subject | View Object

A stereological approach, in which specific, identified regions of cortex were excised as a by-product of therapeutic surgery, revealed an approximately 50% decrease in the number of alpha7-containing neurons in the temporal cortices of patients with AD, without overall loss in neuron number (Banerjee et al., 2000). In addition to loss of neurons, there are reports of reduced expression of specific nAChR subtypes, particularly of alpha4beta2 and alpha7 subunits, in many brain areas in AD. PubMed:19293145

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MeSH
Neurons

path(MESH:"Alzheimer Disease") increases p(HGNC:CHRNA7) View Subject | View Object

It is noteworthy that a different pattern of changes in nAChRs is seen in non-neuronal cells; expression levels of alpha7 have been reported to be elevated in astrocytes of brains from patients with AD and in cultured astrocytes (Teaktong et al., 2003; Xiu et al., 2005; Yu et al., 2005). Likewise, studies comparing alpha7 expression in human AD brain and Swedish-mutant mice found enhanced alpha7 expression in astrocytes but decreased expression in neurons compared with controls (Xiao et al., 2006). PubMed:19293145

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MeSH
Astrocytes

path(MESH:"Alzheimer Disease") decreases p(HGNC:CHRNA7) View Subject | View Object

Thus, predominantly alpha4 and alpha7 subunits, and to a lesser extent alpha3 subunits, are lost in AD, although there are tissue-specific differences to this pattern, such as the upregulation of nAChRs on astrocytes. PubMed:19293145

Appears in Networks:

path(MESH:"Alzheimer Disease") decreases p(HGNC:CHRNA7) View Subject | View Object

Thus, in brains from patients with AD and in neurons responding to exogenously applied Abeta, there is a reduction in expression of nAChR subunits, especially alpha4, alpha7, beta4, and possibly alpha3. Although AD may also involve changes in expression of other ligand-gated ion channels— for example, the expression of NMDA receptors (Bi and Sze, 2002; Jacob et al., 2007), alpha-amino-3-hydroxy- 5-methyl-4-isoxazolepropionic acid receptors (Jacob et al., 2007), and beta3 GABA receptor subunits are all reduced (Mizukami et al., 1998)—there is abundant evidence of a loss of nAChR subunits in AD possibly caused by the actions of Abeta. PubMed:19293145

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MeSH
Brain

path(MESH:"Alzheimer Disease") increases p(HGNC:FYN) View Subject | View Object

FYN expression is increased in brains from patients with AD, specifically in a subset of neurons with elevated hyperphosphorylated tau protein (Shirazi and Wood, 1993), but it is not known whether this increase in FYN contributes to hyperphosphorylation of tau or is a protective response to it. In extracts of human brains from patients with AD, soluble FYN increases with cognitive score and synaptophysin levels and inversely with the tangle count, suggestive of a pro-cognitive role for FYN (Ho et al., 2005). PubMed:19293145

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path(MESH:"Alzheimer Disease") increases p(HGNC:FYN) View Subject | View Object

In a microarray study comparing brains from patients with AD with control brains, FYN was found to be significantly upregulated in AD (Wang et al., 2003a). In this context, it is of interest that FYN has also been shown to activate the PI3K/AKT cascade, thereby inhibiting apoptosis (Tang et al., 2007). Indeed, FYN is required for phos- phorylation of phosphoinositide 3-kinase enhancer (PIKE), which itself regulates AKT (Fig. 3). PIKE binds to AKT and up-regulates its kinase a ctivity, thereby reducing apoptosis. Phosphorylation protects PIKE from caspase cleavage, hence FYN is antiapoptotic (Tang et al., 2007). PubMed:19293145

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path(MESH:"Alzheimer Disease") increases complex(p(HGNC:FYN), p(HGNC:MAPT)) View Subject | View Object

FYN physically interacts with and phosphorylates tau protein, and the affinity of this physical interaction is enhanced in AD-associated mutations in tau protein (Bhaskar et al., 2005). Abeta rapidly induces tyrosine phosphorylation of many proteins (including tau protein) in human and cultured rat cortical neurons (Williamson et al., 2002). This phosphorylation is concomitant with phosphorylation and inactivation of focal adhesion kinase 1 (FADK1, a major downstream target of FYN), is blocked by inhibitors of SRC kinases and PI3K, and involves FYN associating physically with FADK1 (Williamson et al., 2002). PubMed:19293145

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path(MESH:"Alzheimer Disease") association act(p(HGNC:INS)) View Subject | View Object

Shortterm nicotine application also induces phosphorylation of p44/42MAPK, p38MAPK, and STAT-3 and was mediated mostly by alpha7 nAChRs in rat vascular smooth muscle cells (Wada et al., 2007). It is noteworthy that the JAK-2/STAT-3 pathway also mediates the mitogenic effects of insulin, a process recently implicated in AD (Li and Ho¨lscher, 2007). PubMed:19293145

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Cell Ontology (CL)
vascular associated smooth muscle cell

path(MESH:"Alzheimer Disease") association bp(GO:"regulation of cytosolic calcium ion concentration") View Subject | View Object

Recent research interest has focused on the role of calcium dyshomeostasis in AD (Green and LaFerla, 2008); for instance, genetic links with the regulation of cytosolic calcium have been identified (Dreses- Werringloer et al., 2008). Thus nAChRs may provide a link between Abeta and disruption of calcium homeostasis. PubMed:19293145

Appears in Networks:

path(MESH:"Alzheimer Disease") association p(HGNC:PSEN1) View Subject | View Object

APP and APP/presenilin-1 (PS-1) mice do not show neurodegeneration (Irizarry et al., 1997) and yet show several features of AD, including accumulation of plaques and defects in learning (Hsiao et al., 1996), suggesting that many features of AD are not the result of neuronal loss. These animals nonetheless have swollen cholinergic nerve terminals at 12 months, suggesting defective nerve sprouting (Hernandez et al., 2001). PubMed:19293145

Appears in Networks:

path(MESH:"Alzheimer Disease") association bp(GO:learning) View Subject | View Object

APP and APP/presenilin-1 (PS-1) mice do not show neurodegeneration (Irizarry et al., 1997) and yet show several features of AD, including accumulation of plaques and defects in learning (Hsiao et al., 1996), suggesting that many features of AD are not the result of neuronal loss. These animals nonetheless have swollen cholinergic nerve terminals at 12 months, suggesting defective nerve sprouting (Hernandez et al., 2001). PubMed:19293145

Appears in Networks:

path(MESH:"Alzheimer Disease") association path(MESH:"Cognitive Dysfunction") View Subject | View Object

It has long been known that cognitive decline in AD correlates well with synaptic loss (Lue et al., 1999), and it has been shown directly that soluble Abeta inhibits synaptic plasticity (Rowan et al., 2004). PubMed:19293145

Appears in Networks:

path(MESH:"Alzheimer Disease") positiveCorrelation g(HGNC:APOE) View Subject | View Object

The apolipoprotein E type 4 allele (APOE-epsilon4) encodes the APOE lipoprotein, which through its lipid transport function plays a role in lipid metabolism. APOE-epsilon4 has been found to be a major risk factor for late familial or sporadic AD, with a strong gene-dosage effect such that the number of APOE-epsilon4 alleles correlated positively with the risk of developing AD and the age of onset (Corder et al., 1993). PubMed:19293145

Appears in Networks:

path(MESH:"Alzheimer Disease") decreases a(MESH:"Cholinergic Neurons") View Subject | View Object

It is clear that AD involves loss of cholinergic neurons in the brain as well as an overall reduction in nAChRs, and it seems that different subunits are differentially up- or down-regulated in AD in different brain regions and different cell types. PubMed:19293145

Appears in Networks:
Annotations
MeSH
Brain

path(MESH:"Alzheimer Disease") decreases a(MESH:"Cholinergic Neurons") View Subject | View Object

Loss of cholinergic neurons has often been demonstrated as lowered ChAT activity in brains of patients with AD. Early post mortem studies indicated a loss of ChAT activity restricted to the neocortex (Slotkin et al., 1990) and this has been confirmed in more recent studies on frontal lobe and temporal cortex (Lai et al., 2006). It is noteworthy that an increase in ChAT activity in the surviving neurons was interpreted as a possible compensatory mechanism (Slotkin et al., 1990). PubMed:19293145

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MeSH
Frontal Lobe
MeSH
Neocortex
MeSH
Temporal Lobe

path(MESH:"Alzheimer Disease") decreases a(MESH:"Cholinergic Neurons") View Subject | View Object

AD involves loss of cholinergic cells not only in the cortex but also in subcortical nuclei. Up to 50% loss of neurons and of ChAT activity has been reported at autopsy in the locus ceruleus of brains from patients with AD compared with brains from subjects without AD, whereas no change was observed for adrenergic brainstem nuclei (Strong et al., 1991). PubMed:19293145

Appears in Networks:
Annotations
MeSH
Basal Ganglia

path(MESH:"Alzheimer Disease") decreases complex(p(HGNC:CHRNA4), p(HGNC:CHRNB2)) View Subject | View Object

A stereological approach, in which specific, identified regions of cortex were excised as a by-product of therapeutic surgery, revealed an approximately 50% decrease in the number of alpha7-containing neurons in the temporal cortices of patients with AD, without overall loss in neuron number (Banerjee et al., 2000). In addition to loss of neurons, there are reports of reduced expression of specific nAChR subtypes, particularly of alpha4beta2 and alpha7 subunits, in many brain areas in AD. PubMed:19293145

Appears in Networks:
Annotations
MeSH
Neurons

path(MESH:"Alzheimer Disease") decreases act(complex(p(HGNC:CHRNA4), p(HGNC:CHRNB2))) View Subject | View Object

Binding studies using subtypeselective labeled ligands suggest that alpha4beta2 receptors are lost in brains from patients with AD (Warpman and Nordberg, 1995; Martin-Ruiz et al., 1999). Regions showing reduced binding levels include the frontal lobe and the temporal cortex (Lai et al., 2006). PubMed:19293145

Appears in Networks:
Annotations
MeSH
Brain
MeSH
Frontal Lobe
MeSH
Temporal Lobe

path(MESH:"Alzheimer Disease") decreases p(HGNC:CHRNA4) View Subject | View Object

Similar results have been obtained using subtype-specific antibodies. Binding of monoclonal antibodies raised against the alpha4 or the alpha7 subunit, for example, was significantly reduced in post mortem cortices of five patients with AD compared with five patients without AD of similar age (Burghaus et al., 2000). In one study, Western blots confirmed that the greatest reduction was in alpha4 (Guan et al., 2000). Likewise, subunit-specific antibodies reveal a reduced expression of alpha4 but not alpha3 or alpha7 in brains from patients with AD (Martin-Ruiz et al., 1999) PubMed:19293145

Appears in Networks:

path(MESH:"Alzheimer Disease") decreases p(HGNC:CHRNA4) View Subject | View Object

Thus, predominantly alpha4 and alpha7 subunits, and to a lesser extent alpha3 subunits, are lost in AD, although there are tissue-specific differences to this pattern, such as the upregulation of nAChRs on astrocytes. PubMed:19293145

Appears in Networks:

path(MESH:"Alzheimer Disease") decreases p(HGNC:CHRNA4) View Subject | View Object

Thus, in brains from patients with AD and in neurons responding to exogenously applied Abeta, there is a reduction in expression of nAChR subunits, especially alpha4, alpha7, beta4, and possibly alpha3. Although AD may also involve changes in expression of other ligand-gated ion channels— for example, the expression of NMDA receptors (Bi and Sze, 2002; Jacob et al., 2007), alpha-amino-3-hydroxy- 5-methyl-4-isoxazolepropionic acid receptors (Jacob et al., 2007), and beta3 GABA receptor subunits are all reduced (Mizukami et al., 1998)—there is abundant evidence of a loss of nAChR subunits in AD possibly caused by the actions of Abeta. PubMed:19293145

Appears in Networks:
Annotations
MeSH
Brain

path(MESH:"Alzheimer Disease") decreases p(HGNC:CHRNA3) View Subject | View Object

However, a reduction of alpha3 subunits in a Western blot analysis of brains from patients with AD has been observed (Guan et al., 2000), although the loss was not as great as that observed for alpha4 or alpha7 subunits. In addition, alpha3 subunit levels were reduced in the temporal cortex and hippocampus of brains from patients with AD, both smokers and nonsmokers, compared with control subjects (Mousavi et al., 2003). PubMed:19293145

Appears in Networks:
Annotations
MeSH
Hippocampus
MeSH
Temporal Lobe

path(MESH:"Alzheimer Disease") decreases p(HGNC:CHRNA3) View Subject | View Object

Thus, predominantly alpha4 and alpha7 subunits, and to a lesser extent alpha3 subunits, are lost in AD, although there are tissue-specific differences to this pattern, such as the upregulation of nAChRs on astrocytes. PubMed:19293145

Appears in Networks:

path(MESH:"Alzheimer Disease") decreases p(HGNC:CHRNA3) View Subject | View Object

Thus, in brains from patients with AD and in neurons responding to exogenously applied Abeta, there is a reduction in expression of nAChR subunits, especially alpha4, alpha7, beta4, and possibly alpha3. Although AD may also involve changes in expression of other ligand-gated ion channels— for example, the expression of NMDA receptors (Bi and Sze, 2002; Jacob et al., 2007), alpha-amino-3-hydroxy- 5-methyl-4-isoxazolepropionic acid receptors (Jacob et al., 2007), and beta3 GABA receptor subunits are all reduced (Mizukami et al., 1998)—there is abundant evidence of a loss of nAChR subunits in AD possibly caused by the actions of Abeta. PubMed:19293145

Appears in Networks:
Annotations
MeSH
Brain

path(MESH:"Alzheimer Disease") causesNoChange r(HGNCGENEFAMILY:"Cholinergic receptors nicotinic subunits") View Subject | View Object

More recent approaches have confirmed this: RNA profiling of isolated neurons from control brains or brains from patients with AD show no evidence for changes in nAChR RNA (Chow et al., 1998; Ginsberg et al., 2000). PubMed:19293145

Appears in Networks:

path(MESH:"Alzheimer Disease") decreases p(HGNC:CHRNB4) View Subject | View Object

Thus, in brains from patients with AD and in neurons responding to exogenously applied Abeta, there is a reduction in expression of nAChR subunits, especially alpha4, alpha7, beta4, and possibly alpha3. Although AD may also involve changes in expression of other ligand-gated ion channels— for example, the expression of NMDA receptors (Bi and Sze, 2002; Jacob et al., 2007), alpha-amino-3-hydroxy- 5-methyl-4-isoxazolepropionic acid receptors (Jacob et al., 2007), and beta3 GABA receptor subunits are all reduced (Mizukami et al., 1998)—there is abundant evidence of a loss of nAChR subunits in AD possibly caused by the actions of Abeta. PubMed:19293145

Appears in Networks:
Annotations
MeSH
Brain

path(MESH:"Alzheimer Disease") decreases p(HGNCGENEFAMILY:"Glutamate ionotropic receptor NMDA type subunits") View Subject | View Object

Thus, in brains from patients with AD and in neurons responding to exogenously applied Abeta, there is a reduction in expression of nAChR subunits, especially alpha4, alpha7, beta4, and possibly alpha3. Although AD may also involve changes in expression of other ligand-gated ion channels— for example, the expression of NMDA receptors (Bi and Sze, 2002; Jacob et al., 2007), alpha-amino-3-hydroxy- 5-methyl-4-isoxazolepropionic acid receptors (Jacob et al., 2007), and beta3 GABA receptor subunits are all reduced (Mizukami et al., 1998)—there is abundant evidence of a loss of nAChR subunits in AD possibly caused by the actions of Abeta. PubMed:19293145

Appears in Networks:
Annotations
MeSH
Brain

path(MESH:"Alzheimer Disease") decreases p(HGNCGENEFAMILY:"Glutamate ionotropic receptor AMPA type subunits") View Subject | View Object

Thus, in brains from patients with AD and in neurons responding to exogenously applied Abeta, there is a reduction in expression of nAChR subunits, especially alpha4, alpha7, beta4, and possibly alpha3. Although AD may also involve changes in expression of other ligand-gated ion channels— for example, the expression of NMDA receptors (Bi and Sze, 2002; Jacob et al., 2007), alpha-amino-3-hydroxy- 5-methyl-4-isoxazolepropionic acid receptors (Jacob et al., 2007), and beta3 GABA receptor subunits are all reduced (Mizukami et al., 1998)—there is abundant evidence of a loss of nAChR subunits in AD possibly caused by the actions of Abeta. PubMed:19293145

Appears in Networks:
Annotations
MeSH
Brain

path(MESH:"Alzheimer Disease") decreases p(HGNC:GABRB3) View Subject | View Object

Thus, in brains from patients with AD and in neurons responding to exogenously applied Abeta, there is a reduction in expression of nAChR subunits, especially alpha4, alpha7, beta4, and possibly alpha3. Although AD may also involve changes in expression of other ligand-gated ion channels— for example, the expression of NMDA receptors (Bi and Sze, 2002; Jacob et al., 2007), alpha-amino-3-hydroxy- 5-methyl-4-isoxazolepropionic acid receptors (Jacob et al., 2007), and beta3 GABA receptor subunits are all reduced (Mizukami et al., 1998)—there is abundant evidence of a loss of nAChR subunits in AD possibly caused by the actions of Abeta. PubMed:19293145

Appears in Networks:
Annotations
MeSH
Brain

path(MESH:"Alzheimer Disease") causesNoChange p(MGI:Chrna7) View Subject | View Object

Tg2576 mice expressing human Abeta show reduced [3H]cytisine binding (a label of nAChRs) in the cortex at 17 months after birth (Apelt et al., 2002). In contrast, however, levels of alpha7 or alpha4 subunits were unchanged in double-mutant Swedish APP/PS-1 mice as determined by radiolabeled cytosine (alpha4beta2) or alpha-bungarotoxin (alpha7) binding (Marutle et al., 2002). PubMed:19293145

Appears in Networks:

path(MESH:"Alzheimer Disease") causesNoChange p(MGI:Chrna4) View Subject | View Object

Tg2576 mice expressing human Abeta show reduced [3H]cytisine binding (a label of nAChRs) in the cortex at 17 months after birth (Apelt et al., 2002). In contrast, however, levels of alpha7 or alpha4 subunits were unchanged in double-mutant Swedish APP/PS-1 mice as determined by radiolabeled cytosine (alpha4beta2) or alpha-bungarotoxin (alpha7) binding (Marutle et al., 2002). PubMed:19293145

Appears in Networks:

path(MESH:"Alzheimer Disease") association path(MESH:"Psychotic Disorders") View Subject | View Object

Schizophrenia (SZ) and Alzheimer’s disease (AD) are two devastating disorders of the central nervous system (CNS) that present clinically with cognitive impairments and psychotic symptoms PubMed:24511233

Appears in Networks:
Annotations
MeSH
Central Nervous System

path(MESH:"Alzheimer Disease") association path(MESH:"Psychotic Disorders") View Subject | View Object

Conversely, the most commonly associated symptoms of AD are cognitive in nature and include deficits in learning and memory. However, 50%–80% of AD patients display psychotic and behavioral disturbances that are correlated with poor social and functional outcomes PubMed:24511233

Appears in Networks:

path(MESH:"Alzheimer Disease") association path(MESH:"Psychotic Disorders") View Subject | View Object

AD is the most commonly diagnosed form of dementia and currently affects approximately 35 million individuals worldwide.7 AD is a progressive neurodegenerative disease that is characterized by a host of cognitive deficits, including impairments in learning and memory. In addition to the well-documented cognitive impairments, AD patients also display behavioral disturbances, including anxiety, depression, and psychosis PubMed:24511233

Appears in Networks:

path(MESH:"Alzheimer Disease") association path(MESH:"Cognitive Dysfunction") View Subject | View Object

Schizophrenia (SZ) and Alzheimer’s disease (AD) are two devastating disorders of the central nervous system (CNS) that present clinically with cognitive impairments and psychotic symptoms PubMed:24511233

Appears in Networks:
Annotations
MeSH
Central Nervous System

path(MESH:"Alzheimer Disease") association path(MESH:"Cognitive Dysfunction") View Subject | View Object

AD is the most commonly diagnosed form of dementia and currently affects approximately 35 million individuals worldwide.7 AD is a progressive neurodegenerative disease that is characterized by a host of cognitive deficits, including impairments in learning and memory. In addition to the well-documented cognitive impairments, AD patients also display behavioral disturbances, including anxiety, depression, and psychosis PubMed:24511233

Appears in Networks:

path(MESH:"Alzheimer Disease") association bp(GO:cognition) View Subject | View Object

Conversely, the most commonly associated symptoms of AD are cognitive in nature and include deficits in learning and memory. However, 50%–80% of AD patients display psychotic and behavioral disturbances that are correlated with poor social and functional outcomes PubMed:24511233

Appears in Networks:

path(MESH:"Alzheimer Disease") decreases bp(GO:cognition) View Subject | View Object

AD is the most commonly diagnosed form of dementia and currently affects approximately 35 million individuals worldwide.7 AD is a progressive neurodegenerative disease that is characterized by a host of cognitive deficits, including impairments in learning and memory. In addition to the well-documented cognitive impairments, AD patients also display behavioral disturbances, including anxiety, depression, and psychosis PubMed:24511233

Appears in Networks:

path(MESH:"Alzheimer Disease") association bp(GO:learning) View Subject | View Object

Conversely, the most commonly associated symptoms of AD are cognitive in nature and include deficits in learning and memory. However, 50%–80% of AD patients display psychotic and behavioral disturbances that are correlated with poor social and functional outcomes PubMed:24511233

Appears in Networks:

path(MESH:"Alzheimer Disease") decreases bp(GO:learning) View Subject | View Object

AD is the most commonly diagnosed form of dementia and currently affects approximately 35 million individuals worldwide.7 AD is a progressive neurodegenerative disease that is characterized by a host of cognitive deficits, including impairments in learning and memory. In addition to the well-documented cognitive impairments, AD patients also display behavioral disturbances, including anxiety, depression, and psychosis PubMed:24511233

Appears in Networks:

path(MESH:"Alzheimer Disease") association bp(GO:memory) View Subject | View Object

Conversely, the most commonly associated symptoms of AD are cognitive in nature and include deficits in learning and memory. However, 50%–80% of AD patients display psychotic and behavioral disturbances that are correlated with poor social and functional outcomes PubMed:24511233

Appears in Networks:

path(MESH:"Alzheimer Disease") decreases bp(GO:"synaptic transmission, cholinergic") View Subject | View Object

Another commonality between AD and SZ is the apparent involvement of dysregulated cholinergic signaling in the brain. PubMed:24511233

Appears in Networks:

path(MESH:"Alzheimer Disease") decreases bp(GO:"synaptic transmission, cholinergic") View Subject | View Object

1 Several lines of evidence suggest that impaired cholinergic signaling plays a key role in mediating both the cognitive and the behavioral impairments observed in AD patients.12 The basal forebrain cholinergic system is disproportionately affected in AD patients, with a robust loss of cholinergic neurons, including those innervating the hippocampus and cortex. PubMed:24511233

Appears in Networks:

path(MESH:"Alzheimer Disease") association path(MESH:Dementia) View Subject | View Object

AD is the most commonly diagnosed form of dementia and currently affects approximately 35 million individuals worldwide.7 AD is a progressive neurodegenerative disease that is characterized by a host of cognitive deficits, including impairments in learning and memory. In addition to the well-documented cognitive impairments, AD patients also display behavioral disturbances, including anxiety, depression, and psychosis PubMed:24511233

Appears in Networks:

path(MESH:"Alzheimer Disease") isA path(MESH:"Neurodegenerative Diseases") View Subject | View Object

Appears in Networks:

path(MESH:"Alzheimer Disease") increases path(MESH:Depression) View Subject | View Object

AD is the most commonly diagnosed form of dementia and currently affects approximately 35 million individuals worldwide.7 AD is a progressive neurodegenerative disease that is characterized by a host of cognitive deficits, including impairments in learning and memory. In addition to the well-documented cognitive impairments, AD patients also display behavioral disturbances, including anxiety, depression, and psychosis PubMed:24511233

Appears in Networks:

path(MESH:"Alzheimer Disease") increases path(MESH:Anxiety) View Subject | View Object

AD is the most commonly diagnosed form of dementia and currently affects approximately 35 million individuals worldwide.7 AD is a progressive neurodegenerative disease that is characterized by a host of cognitive deficits, including impairments in learning and memory. In addition to the well-documented cognitive impairments, AD patients also display behavioral disturbances, including anxiety, depression, and psychosis PubMed:24511233

Appears in Networks:

path(MESH:"Alzheimer Disease") association bp(MESH:Aging) View Subject | View Object

Age is the primary risk factor for AD, and the disease usually manifests in individuals after the age of 60 years. Due to an aging population, the prevalence of AD is predicted to rise to 66 million people by the year 2030. PubMed:24511233

Appears in Networks:

path(MESH:"Alzheimer Disease") decreases a(MESH:"Cholinergic Neurons") View Subject | View Object

1 Several lines of evidence suggest that impaired cholinergic signaling plays a key role in mediating both the cognitive and the behavioral impairments observed in AD patients.12 The basal forebrain cholinergic system is disproportionately affected in AD patients, with a robust loss of cholinergic neurons, including those innervating the hippocampus and cortex. PubMed:24511233

Appears in Networks:
Annotations
MeSH
Cerebral Cortex
MeSH
Hippocampus

path(MESH:"Alzheimer Disease") association p(FPLX:CHRN) View Subject | View Object

Decline, disruption, or alterations of nicotinic cholinergic mechanisms have been implicated in various dysfunctions, such as schizophrenia, epilepsy, autism, Alzheimer’s disease (AD), and addiction (17–23). PubMed:17009926

Appears in Networks:

path(MESH:"Alzheimer Disease") negativeCorrelation act(p(FPLX:CHRN)) View Subject | View Object

Nicotinic mechanisms contribute to cognitive function, and the decline of nicotinic mechanisms or loss of nAChRs has been observed in AD, dementia with Lewy bodies, Down syndrome, autism, and Parkinson’s disease (20, 140). PubMed:17009926

Appears in Networks:

path(MESH:"Alzheimer Disease") negativeCorrelation p(FPLX:CHRN) View Subject | View Object

Nicotinic mechanisms contribute to cognitive function, and the decline of nicotinic mechanisms or loss of nAChRs has been observed in AD, dementia with Lewy bodies, Down syndrome, autism, and Parkinson’s disease (20, 140). PubMed:17009926

Appears in Networks:

path(MESH:"Alzheimer Disease") negativeCorrelation p(FPLX:CHRN) View Subject | View Object

As AD worsens, cholinergic neurons are progressively lost and the number of nAChRs declines, particularly in the hippocampus and cortex (140, 158). PubMed:17009926

Appears in Networks:
Annotations
Cell Ontology (CL)
cholinergic neuron
MeSH
Cerebral Cortex
MeSH
Hippocampus
MeSH
Alzheimer Disease

path(MESH:"Alzheimer Disease") positiveCorrelation bp(GO:"neuron death") View Subject | View Object

The most well-appreciated neuronal loss, however, is in the cholinergic system (155, 156), particularly the basal forebrain cholinergic system comprised of the medial septal nucleus, the horizontal and vertical diagonal bands of Broca, and the nucleus basalis of Meynert (157). PubMed:17009926

Appears in Networks:
Annotations
Cell Ontology (CL)
cholinergic neuron
MeSH
Alzheimer Disease

path(MESH:"Alzheimer Disease") positiveCorrelation bp(GO:"neuron death") View Subject | View Object

As AD worsens, cholinergic neurons are progressively lost and the number of nAChRs declines, particularly in the hippocampus and cortex (140, 158). PubMed:17009926

Appears in Networks:
Annotations
Cell Ontology (CL)
cholinergic neuron
MeSH
Cerebral Cortex
MeSH
Hippocampus
MeSH
Alzheimer Disease

path(MESH:"Alzheimer Disease") association complex(a(CHEBI:"amyloid-beta polypeptide 42"), p(HGNC:CHRNA7)) View Subject | View Object

Although Aβ peptides negatively alter the cholinergic system at multiple sites, including ACh synthesis, ACh release, and muscarinic receptors (157), the discovery that Aβ1−42 binds to α7 nAChRs with high affinity suggested the potential for a causal role of nAChRs in AD (159, 160). PubMed:17009926

Appears in Networks:
Annotations
MeSH
Alzheimer Disease

path(MESH:"Alzheimer Disease") increases deg(a(MESH:"Basal Nucleus of Meynert")) View Subject | View Object

Importantly, the neurons that form the nucleus basalis of Meynert undergo extensive degeneration in AD PubMed:26813123

Appears in Networks:

path(MESH:"Alzheimer Disease") negativeCorrelation a(MESH:"Basal Nucleus of Meynert") View Subject | View Object

The loss of the nucleus basalis cholinergic neurons in AD patients is severe: from about 500,000 in the healthy adult to less than 100,000 in patients displaying advanced AD PubMed:26813123

Appears in Networks:

path(MESH:"Alzheimer Disease") association bp(GO:"synaptic transmission, cholinergic") View Subject | View Object

Because ACh has an important role in cognitive processes, the cholinergic system is pointed as an important factor in many forms of dementia, including AD PubMed:26813123

Appears in Networks:

path(MESH:"Alzheimer Disease") positiveCorrelation path(MESH:Apathy) View Subject | View Object

In addition to cognitive alterations, psychiatric symptoms are frequently observed in AD patients, including apathy and depression PubMed:26813123

Appears in Networks:
Annotations
MeSH
CA3 Region, Hippocampal

path(MESH:"Alzheimer Disease") positiveCorrelation path(MESH:Depression) View Subject | View Object

In addition to cognitive alterations, psychiatric symptoms are frequently observed in AD patients, including apathy and depression PubMed:26813123

Appears in Networks:
Annotations
MeSH
CA3 Region, Hippocampal

path(MESH:"Alzheimer Disease") positiveCorrelation path(MESH:"Cognitive Dysfunction") View Subject | View Object

In addition to cognitive alterations, psychiatric symptoms are frequently observed in AD patients, including apathy and depression PubMed:26813123

Appears in Networks:
Annotations
MeSH
CA3 Region, Hippocampal

path(MESH:"Alzheimer Disease") negativeCorrelation a(MESH:"Cholinergic Neurons") View Subject | View Object

Further highlighting the importance of the cholinergic system in the CNS, cholinergic neuronal loss, especially in the basal forebrain, occurs not only in AD, but also in Parkinson’s disease [190, 191], Down syndrome [192], amyotrophic lateral sclerosis [193, 194], progressive supranuclear palsy [195, 196], and olivopontocerebellar atrophy [197] PubMed:26813123

Appears in Networks:
Annotations
MeSH
Basal Forebrain
MeSH
Central Nervous System

path(MESH:"Alzheimer Disease") decreases act(p(HGNC:CHAT)) View Subject | View Object

Moreover, it has been demonstrated that ChAT transcription is severely diminished in the remaining cholinergic neurons, which leads to decreased ChAT activity and progression of dementia PubMed:26813123

Appears in Networks:

path(MESH:"Alzheimer Disease") association p(HGNC:ACHE) View Subject | View Object

Furthermore, some evidences also suggest the involvement of AChE in the pathogenesis of AD PubMed:26813123

Appears in Networks:

path(MESH:"Alzheimer Disease") negativeCorrelation a(CHEBI:rivastigmine) View Subject | View Object

Rivastigmine has also been used for AD treatment due to its ease of use (transdermal patch) and good tolerability by patients PubMed:26813123

Appears in Networks:
Annotations
MeSH
Alzheimer Disease

path(MESH:"Alzheimer Disease") negativeCorrelation complex(p(HGNC:CHRM1), p(INTERPRO:"G-protein alpha subunit, group Q")) View Subject | View Object

It has been demonstrated that M1 muscarinic receptors coupling to G-proteins is impaired in the neocortex of AD patients and that the extent of M1/G-protein uncoupling is related to the severity of cognitive symptoms in AD PubMed:26813123

Appears in Networks:
Annotations
MeSH
Neocortex
MeSH
Alzheimer Disease

path(MESH:"Alzheimer Disease") isA path(MESH:"Neurodegenerative Diseases") View Subject | View Object

Appears in Networks:

path(MESH:"Alzheimer Disease") decreases bp(GO:cognition) View Subject | View Object

Alzheimer’s disease (AD) is a debilitating neurodegenerative disorder afflicting millions of people. It is diagnosed by the progressive loss of cognitive function and behavioral defi cits and is characterized by the presence of neurofibrillary tangles (NFTs), senile plaques, cholinergic neuron loss, and neuronal atrophy at autopsy PubMed:24590577

Appears in Networks:

path(MESH:"Alzheimer Disease") association path(MESH:"Plaque, Amyloid") View Subject | View Object

Alzheimer’s disease (AD) is a debilitating neurodegenerative disorder afflicting millions of people. It is diagnosed by the progressive loss of cognitive function and behavioral defi cits and is characterized by the presence of neurofibrillary tangles (NFTs), senile plaques, cholinergic neuron loss, and neuronal atrophy at autopsy PubMed:24590577

Appears in Networks:

path(MESH:"Alzheimer Disease") association path(MESH:"Neurofibrillary Tangles") View Subject | View Object

Alzheimer’s disease (AD) is a debilitating neurodegenerative disorder afflicting millions of people. It is diagnosed by the progressive loss of cognitive function and behavioral defi cits and is characterized by the presence of neurofibrillary tangles (NFTs), senile plaques, cholinergic neuron loss, and neuronal atrophy at autopsy PubMed:24590577

Appears in Networks:

path(MESH:"Alzheimer Disease") decreases a(MESH:"Cholinergic Neurons") View Subject | View Object

Alzheimer’s disease (AD) is a debilitating neurodegenerative disorder afflicting millions of people. It is diagnosed by the progressive loss of cognitive function and behavioral defi cits and is characterized by the presence of neurofibrillary tangles (NFTs), senile plaques, cholinergic neuron loss, and neuronal atrophy at autopsy PubMed:24590577

Appears in Networks:

path(MESH:"Alzheimer Disease") decreases a(MESH:"Cholinergic Neurons") View Subject | View Object

The third important hallmark of AD is cholinergic hypofunction. The neurotransmitter acetylcholine (ACh) exerts its physiological functions by activating either ionotropic nicotinic ACh receptors (nAChRs) or metabotropic muscarinic ACh receptors (mAChRs). It has been reported that in AD brains there are (1) reduced choline acetyltransferase levels accompanied by decreased ACh synthesis; (2) significant loss of cholinergic neurons; (3) reduction in the numbers of postsynaptic neurons accessible to ACh; (4) cholinergic neuronal and axonal abnormalities; and (5) reduction in nAChR levels PubMed:24590577

Appears in Networks:

path(MESH:"Alzheimer Disease") increases bp(GO:"neuron death") View Subject | View Object

Alzheimer’s disease (AD) is a debilitating neurodegenerative disorder afflicting millions of people. It is diagnosed by the progressive loss of cognitive function and behavioral defi cits and is characterized by the presence of neurofibrillary tangles (NFTs), senile plaques, cholinergic neuron loss, and neuronal atrophy at autopsy PubMed:24590577

Appears in Networks:

path(MESH:"Alzheimer Disease") decreases bp(GO:"synaptic transmission, cholinergic") View Subject | View Object

The third important hallmark of AD is cholinergic hypofunction. The neurotransmitter acetylcholine (ACh) exerts its physiological functions by activating either ionotropic nicotinic ACh receptors (nAChRs) or metabotropic muscarinic ACh receptors (mAChRs). It has been reported that in AD brains there are (1) reduced choline acetyltransferase levels accompanied by decreased ACh synthesis; (2) significant loss of cholinergic neurons; (3) reduction in the numbers of postsynaptic neurons accessible to ACh; (4) cholinergic neuronal and axonal abnormalities; and (5) reduction in nAChR levels PubMed:24590577

Appears in Networks:

path(MESH:"Alzheimer Disease") decreases p(HGNC:CHAT) View Subject | View Object

The third important hallmark of AD is cholinergic hypofunction. The neurotransmitter acetylcholine (ACh) exerts its physiological functions by activating either ionotropic nicotinic ACh receptors (nAChRs) or metabotropic muscarinic ACh receptors (mAChRs). It has been reported that in AD brains there are (1) reduced choline acetyltransferase levels accompanied by decreased ACh synthesis; (2) significant loss of cholinergic neurons; (3) reduction in the numbers of postsynaptic neurons accessible to ACh; (4) cholinergic neuronal and axonal abnormalities; and (5) reduction in nAChR levels PubMed:24590577

Appears in Networks:

path(MESH:"Alzheimer Disease") decreases p(HGNCGENEFAMILY:"Cholinergic receptors nicotinic subunits") View Subject | View Object

The third important hallmark of AD is cholinergic hypofunction. The neurotransmitter acetylcholine (ACh) exerts its physiological functions by activating either ionotropic nicotinic ACh receptors (nAChRs) or metabotropic muscarinic ACh receptors (mAChRs). It has been reported that in AD brains there are (1) reduced choline acetyltransferase levels accompanied by decreased ACh synthesis; (2) significant loss of cholinergic neurons; (3) reduction in the numbers of postsynaptic neurons accessible to ACh; (4) cholinergic neuronal and axonal abnormalities; and (5) reduction in nAChR levels PubMed:24590577

Appears in Networks:

path(MESH:"Alzheimer Disease") association p(HGNCGENEFAMILY:"Cholinergic receptors muscarinic") View Subject | View Object

Recent evidence indicates that cholinergic hypofunction is closely linked to Abeta and tau pathologies[20]. As a major receptor group for ACh, mAChRs have also been implicated in the pathophysiology of AD. PubMed:24590577

Appears in Networks:

path(MESH:"Alzheimer Disease") positiveCorrelation complex(p(HGNC:CHRNA7), p(HGNC:FLNA)) View Subject | View Object

Wang et al. showed that the association between FLNA and the alpha7 subunit is elevated in AD samples compared to age matched controls PubMed:25514383

Appears in Networks:

path(MESH:"Alzheimer Disease") association path(MESH:Dementia) View Subject | View Object

Dementia is a debilitating condition frequent in ageing populations, and Alzheimer's Disease (AD) accounts for 70% of all dementia cases. AD is characterized by neuropathological hallmarks consisting of an accumulation of Amyloid beta peptide (Ab) in extracellular plaques, intracellular deposits of tau protein, neuronal loss and, more recently, a prominent synaptic loss was identified (Braak and Braak,1991; Masliah et al., 2001; Selkoe,1991; Spires-Jones and Hyman, 2014) PubMed:25514383

Appears in Networks:

path(MESH:"Alzheimer Disease") positiveCorrelation path(MESH:"Plaque, Amyloid") View Subject | View Object

Dementia is a debilitating condition frequent in ageing populations, and Alzheimer's Disease (AD) accounts for 70% of all dementia cases. AD is characterized by neuropathological hallmarks consisting of an accumulation of Amyloid beta peptide (Ab) in extracellular plaques, intracellular deposits of tau protein, neuronal loss and, more recently, a prominent synaptic loss was identified (Braak and Braak,1991; Masliah et al., 2001; Selkoe,1991; Spires-Jones and Hyman, 2014) PubMed:25514383

Appears in Networks:

path(MESH:"Alzheimer Disease") positiveCorrelation p(HGNC:MAPT) View Subject | View Object

Dementia is a debilitating condition frequent in ageing populations, and Alzheimer's Disease (AD) accounts for 70% of all dementia cases. AD is characterized by neuropathological hallmarks consisting of an accumulation of Amyloid beta peptide (Ab) in extracellular plaques, intracellular deposits of tau protein, neuronal loss and, more recently, a prominent synaptic loss was identified (Braak and Braak,1991; Masliah et al., 2001; Selkoe,1991; Spires-Jones and Hyman, 2014) PubMed:25514383

Appears in Networks:

path(MESH:"Alzheimer Disease") positiveCorrelation bp(GO:"neuron death") View Subject | View Object

Dementia is a debilitating condition frequent in ageing populations, and Alzheimer's Disease (AD) accounts for 70% of all dementia cases. AD is characterized by neuropathological hallmarks consisting of an accumulation of Amyloid beta peptide (Ab) in extracellular plaques, intracellular deposits of tau protein, neuronal loss and, more recently, a prominent synaptic loss was identified (Braak and Braak,1991; Masliah et al., 2001; Selkoe,1991; Spires-Jones and Hyman, 2014) PubMed:25514383

Appears in Networks:

path(MESH:"Alzheimer Disease") negativeCorrelation a(GO:synapse) View Subject | View Object

Dementia is a debilitating condition frequent in ageing populations, and Alzheimer's Disease (AD) accounts for 70% of all dementia cases. AD is characterized by neuropathological hallmarks consisting of an accumulation of Amyloid beta peptide (Ab) in extracellular plaques, intracellular deposits of tau protein, neuronal loss and, more recently, a prominent synaptic loss was identified (Braak and Braak,1991; Masliah et al., 2001; Selkoe,1991; Spires-Jones and Hyman, 2014) PubMed:25514383

Appears in Networks:

path(MESH:"Alzheimer Disease") negativeCorrelation a(MESH:"White Matter") View Subject | View Object

In addition, anatomical studies in AD patients showed a massive loss of brain white matter and a specific reduction of cholinergic neurons of the basal forebrain (Auld et al., 2002; Bowen et al., 1976; Coyle et al., 1983; Kim et al., 2013; Whitehouse et al., 1981, 1982) PubMed:25514383

Appears in Networks:
Annotations
MeSH
Brain

path(MESH:"Alzheimer Disease") negativeCorrelation a(HP:"cholinergic neuron") View Subject | View Object

In addition, anatomical studies in AD patients showed a massive loss of brain white matter and a specific reduction of cholinergic neurons of the basal forebrain (Auld et al., 2002; Bowen et al., 1976; Coyle et al., 1983; Kim et al., 2013; Whitehouse et al., 1981, 1982) PubMed:25514383

Appears in Networks:
Annotations
MeSH
Basal Forebrain

path(MESH:"Alzheimer Disease") decreases complex(a(CHEBI:acetylcholine), p(FPLX:CHRN)) View Subject | View Object

Binding studies performed with the use of [3H]-nicotine and [3H]-ACh showed a significant reduction in nicotine and ACh binding sites in cerebral cortex of patients suffering from AD, demonstrating a decrease of both nAChR and mAChR populations (Gotti et al., 2006a; Paterson and Nordberg, 2000; Perry et al., 1981, 1985, 1987, 1988; Shimohama et al., 1986; Whitehouse et al., 1981, 1982, 1986) PubMed:25514383

Appears in Networks:
Annotations
MeSH
Cerebral Cortex

path(MESH:"Alzheimer Disease") decreases complex(a(CHEBI:acetylcholine), p(FPLX:CHRM)) View Subject | View Object

Binding studies performed with the use of [3H]-nicotine and [3H]-ACh showed a significant reduction in nicotine and ACh binding sites in cerebral cortex of patients suffering from AD, demonstrating a decrease of both nAChR and mAChR populations (Gotti et al., 2006a; Paterson and Nordberg, 2000; Perry et al., 1981, 1985, 1987, 1988; Shimohama et al., 1986; Whitehouse et al., 1981, 1982, 1986) PubMed:25514383

Appears in Networks:
Annotations
MeSH
Cerebral Cortex

path(MESH:"Alzheimer Disease") decreases complex(a(CHEBI:nicotine), p(FPLX:CHRN)) View Subject | View Object

Binding studies performed with the use of [3H]-nicotine and [3H]-ACh showed a significant reduction in nicotine and ACh binding sites in cerebral cortex of patients suffering from AD, demonstrating a decrease of both nAChR and mAChR populations (Gotti et al., 2006a; Paterson and Nordberg, 2000; Perry et al., 1981, 1985, 1987, 1988; Shimohama et al., 1986; Whitehouse et al., 1981, 1982, 1986) PubMed:25514383

Appears in Networks:
Annotations
MeSH
Cerebral Cortex

path(MESH:"Alzheimer Disease") decreases complex(a(CHEBI:nicotine), p(FPLX:CHRM)) View Subject | View Object

Binding studies performed with the use of [3H]-nicotine and [3H]-ACh showed a significant reduction in nicotine and ACh binding sites in cerebral cortex of patients suffering from AD, demonstrating a decrease of both nAChR and mAChR populations (Gotti et al., 2006a; Paterson and Nordberg, 2000; Perry et al., 1981, 1985, 1987, 1988; Shimohama et al., 1986; Whitehouse et al., 1981, 1982, 1986) PubMed:25514383

Appears in Networks:
Annotations
MeSH
Cerebral Cortex

path(MESH:"Alzheimer Disease") decreases p(FPLX:CHRN) View Subject | View Object

Binding studies performed with the use of [3H]-nicotine and [3H]-ACh showed a significant reduction in nicotine and ACh binding sites in cerebral cortex of patients suffering from AD, demonstrating a decrease of both nAChR and mAChR populations (Gotti et al., 2006a; Paterson and Nordberg, 2000; Perry et al., 1981, 1985, 1987, 1988; Shimohama et al., 1986; Whitehouse et al., 1981, 1982, 1986) PubMed:25514383

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Cerebral Cortex

path(MESH:"Alzheimer Disease") decreases p(FPLX:CHRM) View Subject | View Object

Binding studies performed with the use of [3H]-nicotine and [3H]-ACh showed a significant reduction in nicotine and ACh binding sites in cerebral cortex of patients suffering from AD, demonstrating a decrease of both nAChR and mAChR populations (Gotti et al., 2006a; Paterson and Nordberg, 2000; Perry et al., 1981, 1985, 1987, 1988; Shimohama et al., 1986; Whitehouse et al., 1981, 1982, 1986) PubMed:25514383

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Cerebral Cortex

path(MESH:"Alzheimer Disease") decreases act(p(HGNC:CHAT)) View Subject | View Object

In addition to nAChRs and mAChRs, the enzyme choline acetyltransferase (ChAT), involved in ACh production, is also affected in AD. The activity of this ChAT enzyme, and consequently the synthesis of ACh, is decreased in AD brains PubMed:25514383

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MeSH
Brain

path(MESH:"Alzheimer Disease") decreases a(CHEBI:acetylcholine) View Subject | View Object

In addition to nAChRs and mAChRs, the enzyme choline acetyltransferase (ChAT), involved in ACh production, is also affected in AD. The activity of this ChAT enzyme, and consequently the synthesis of ACh, is decreased in AD brains PubMed:25514383

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Brain

path(MESH:"Alzheimer Disease") positiveCorrelation a(CHEBI:"amyloid-beta") View Subject | View Object

With the progression of the disease the amount of Abeta increases, it starts to accumulate, and becomes toxic for the neurons (Hernandez et al., 2010) PubMed:25514383

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MeSH
Alzheimer Disease

path(MESH:"Alzheimer Disease") positiveCorrelation a(HBP:"amyloid-beta aggregates") View Subject | View Object

With the progression of the disease the amount of Abeta increases, it starts to accumulate, and becomes toxic for the neurons (Hernandez et al., 2010) PubMed:25514383

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MeSH
Alzheimer Disease

path(MESH:"Alzheimer Disease") increases path(MESH:"Cognitive Dysfunction") View Subject | View Object

Several studies showed that in AD animal models, the appearance of the cognitive deficits precedes plaque deposition (Casas et al., 2004; Gouras et al., 2000; Kumar et al., 2013; Wirths et al., 2004) PubMed:27522251

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MeSH
Alzheimer Disease

path(MESH:"Alzheimer Disease") increases path(MESH:Dementia) View Subject | View Object

Alzheimer’s disease (AD) is the leading cause of dementia in the elderly. PubMed:21718217

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Confidence
High

path(MESH:"Alzheimer Disease") association a(HBP:HBP00018) View Subject | View Object

AD is a chronic neurodegenerative disease characterized by the progressive deposition of the amyloid b (Ab) in the parenchyma of the brain. PubMed:21718217

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Confidence
High

path(MESH:"Alzheimer Disease") positiveCorrelation a(HBP:HBP00030) View Subject | View Object

The ApoE4 allele is most important genetic risk factor for AD, while the ApoE2 allele is thought to be protective. PubMed:21718217

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Confidence
High
MeSH
Microglia

path(MESH:"Alzheimer Disease") positiveCorrelation r(HGNC:ARG1) View Subject | View Object

In this study, it was shown that samples from human AD brains as well as two aged mouse models of AD showed increased mRNA levels of the M2 markers, Arg1 and Ym1, when compared to age matched controls [101]. PubMed:21718217

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Confidence
High

path(MESH:"Alzheimer Disease") positiveCorrelation r(HGNC:CHI3L1) View Subject | View Object

In this study, it was shown that samples from human AD brains as well as two aged mouse models of AD showed increased mRNA levels of the M2 markers, Arg1 and Ym1, when compared to age matched controls [101]. PubMed:21718217

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Confidence
High

path(MESH:"Alzheimer Disease") association p(HBP:HBP00030) View Subject | View Object

The ApoE4 allele is most important genetic risk factor for AD, while the ApoE2 allele is thought to be protective. PubMed:21718217

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Confidence
Medium

path(MESH:"Alzheimer Disease") decreases act(p(HGNC:ACHE)) View Subject | View Object

Positron emission tomography studies have revealed a reduced cortical acetylcholinesteserase activity in AD patients (Iyo et al 1997; Kuhl et al 1999) PubMed:11230871

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MeSH
Cerebral Cortex

path(MESH:"Alzheimer Disease") association p(FPLX:CHRN) View Subject | View Object

The nAChRs are found to be involved in a complex range of central nervous system disorders including Alzheimer’s disease (AD), Parkinson’s disease, schizophrenia, Tourette’s syndrome, anxiety, depression, and epilepsy (Newhouse and Kelton 2000; Newhouse et al 1997; Paterson and Nordberg 2000) PubMed:11230871

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path(MESH:"Alzheimer Disease") negativeCorrelation p(FPLX:CHRN) View Subject | View Object

A consistent, significant loss of nAChRs has been observed in cortical autopsy brain tissue from AD patients relative to age-matched healthy subjects (Nordberg and Winblad 1986) PubMed:11230871

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Cerebral Cortex
MeSH
Alzheimer Disease

path(MESH:"Alzheimer Disease") negativeCorrelation p(HGNC:CHRNA3) View Subject | View Object

When the laminar binding distribution of [3H]nicotine, [3H]epibatidine, and [3H]cytisine was measured in AD cortical autopsy tissue, marked reductions were observed relative to control brains (Sihver et al 1999c) (Figure 1) PubMed:11230871

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MeSH
Cerebral Cortex
MeSH
Alzheimer Disease

path(MESH:"Alzheimer Disease") negativeCorrelation p(HGNC:CHRNA3) View Subject | View Object

A decrease in the protein levels of the alpha3 and alpha4 nAChR subunits was recently measured in the temporal cortex and of the alpha3, alpha4, and alpha7 nAChR subtypes in the hippocampi of AD brains relative to age-matched control subjects (Guan et al 2000b) PubMed:11230871

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MeSH
Temporal Lobe

path(MESH:"Alzheimer Disease") negativeCorrelation p(HGNC:CHRNA4) View Subject | View Object

A decrease in the protein levels of the alpha3 and alpha4 nAChR subunits was recently measured in the temporal cortex and of the alpha3, alpha4, and alpha7 nAChR subtypes in the hippocampi of AD brains relative to age-matched control subjects (Guan et al 2000b) PubMed:11230871

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Temporal Lobe

path(MESH:"Alzheimer Disease") negativeCorrelation p(HGNC:CHRNA7) View Subject | View Object

A decrease in the protein levels of the alpha3 and alpha4 nAChR subunits was recently measured in the temporal cortex and of the alpha3, alpha4, and alpha7 nAChR subtypes in the hippocampi of AD brains relative to age-matched control subjects (Guan et al 2000b) PubMed:11230871

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MeSH
Hippocampus

path(MESH:"Alzheimer Disease") negativeCorrelation a(HBP:"alpha-4-containing nAChR") View Subject | View Object

A decrease in protein levels of the alpha4 nAChR but not of the alpha3 and alpha7 nAChRs was reported by Martin-Ruiz et al (1999) PubMed:11230871

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path(MESH:"Alzheimer Disease") negativeCorrelation a(HBP:"alpha-7-containing nAChR") View Subject | View Object

Lee et al (2000) recently also reported a significant decrease in the alpha7 nAChR protein level of the AD hippocampus PubMed:11230871

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MeSH
Hippocampus

path(MESH:"Alzheimer Disease") positiveCorrelation r(HGNC:CHRNA7) View Subject | View Object

Examination of the regional expression of mRNA of the nAChR alpha4 and alpha3 subunits has shown no difference in autopsy AD brain tissue in any region analyzed (Hellstro ¨m-Lindahl et al 1999; Terzano et al 1998), whereas the level of the alpha7 mRNA was significantly higher in the hippocampus (Hellstro¨m-Lindahl et al 1999) PubMed:11230871

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MeSH
Hippocampus

path(MESH:"Alzheimer Disease") causesNoChange r(HGNC:CHRNA3) View Subject | View Object

Examination of the regional expression of mRNA of the nAChR alpha4 and alpha3 subunits has shown no difference in autopsy AD brain tissue in any region analyzed (Hellstro ¨m-Lindahl et al 1999; Terzano et al 1998), whereas the level of the alpha7 mRNA was significantly higher in the hippocampus (Hellstro¨m-Lindahl et al 1999) PubMed:11230871

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MeSH
Hippocampus

path(MESH:"Alzheimer Disease") causesNoChange r(HGNC:CHRNA4) View Subject | View Object

Examination of the regional expression of mRNA of the nAChR alpha4 and alpha3 subunits has shown no difference in autopsy AD brain tissue in any region analyzed (Hellstro ¨m-Lindahl et al 1999; Terzano et al 1998), whereas the level of the alpha7 mRNA was significantly higher in the hippocampus (Hellstro¨m-Lindahl et al 1999) PubMed:11230871

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MeSH
Hippocampus

path(MESH:"Alzheimer Disease") negativeCorrelation act(p(HGNC:ACHE)) View Subject | View Object

A progressive loss of cortical acetylcholinesterase activity has been observed in AD patients with cognitive decline (Shinotoh et al 2000) PubMed:11230871

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MeSH
Cerebral Cortex

path(MESH:"Alzheimer Disease") decreases act(p(HGNC:ACHE)) View Subject | View Object

The loss in cortical acetylcholinesterase activity was less pronounced in mildly demented AD patients relative to autopsy material and did not strictly correlate with cerebral glucose metabolism impairment (Kuhl et al 1999) PubMed:11230871

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path(MESH:"Alzheimer Disease") negativeCorrelation bp(GO:cognition) View Subject | View Object

A progressive loss of cortical acetylcholinesterase activity has been observed in AD patients with cognitive decline (Shinotoh et al 2000) PubMed:11230871

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MeSH
Cerebral Cortex

path(MESH:"Alzheimer Disease") decreases complex(a(CHEBI:nicotine), p(FPLX:CHRN)) View Subject | View Object

Selective cortical deficits in [11C]nicotine binding are often observed by PET early in the course of the AD disease (Figure 3A) PubMed:11230871

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path(MESH:"Alzheimer Disease") decreases a(HBP:"alpha-4 beta-2 nAChR") View Subject | View Object

A ligand with a selectivity for the alpha4beta2 nAChRs would be particularly preferable because the alpha4beta2 has been recognized as the predominant subtype that is deficient in AD (for a review, see Sihver et al 2000) PubMed:11230871

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path(MESH:"Alzheimer Disease") negativeCorrelation p(MGI:Chrna7) View Subject | View Object

Post hoc analysis revealed that, levels of the a7 nAChR protein in normal saline-treated AD mice were significantly lower than its level in the control animals (p<0.001). PubMed:25881725

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path(MESH:"Alzheimer Disease") decreases bp(GO:cognition) View Subject | View Object

Alzheimer’s disease is characterized by progressive cognitive decline, accompanied by a loss of neurons and synapses — especially cholinergic synapses — in the basal forebrain, cerebral cortex and hippocampus126 and by a substantial reduction in both muscarinic and nicotinic AChR expression127. PubMed:19721446

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MeSH
Basal Forebrain
MeSH
Cerebral Cortex
MeSH
Hippocampus
Text Location
Review

path(MESH:"Alzheimer Disease") decreases a(MESH:Neurons) View Subject | View Object

Alzheimer’s disease is characterized by progressive cognitive decline, accompanied by a loss of neurons and synapses — especially cholinergic synapses — in the basal forebrain, cerebral cortex and hippocampus126 and by a substantial reduction in both muscarinic and nicotinic AChR expression127. PubMed:19721446

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MeSH
Basal Forebrain
MeSH
Cerebral Cortex
MeSH
Hippocampus
Text Location
Review

path(MESH:"Alzheimer Disease") decreases p(HGNCGENEFAMILY:"Cholinergic receptors muscarinic") View Subject | View Object

Alzheimer’s disease is characterized by progressive cognitive decline, accompanied by a loss of neurons and synapses — especially cholinergic synapses — in the basal forebrain, cerebral cortex and hippocampus126 and by a substantial reduction in both muscarinic and nicotinic AChR expression127. PubMed:19721446

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MeSH
Basal Forebrain
MeSH
Cerebral Cortex
MeSH
Hippocampus
Text Location
Review

path(MESH:"Alzheimer Disease") decreases p(HGNCGENEFAMILY:"Cholinergic receptors nicotinic subunits") View Subject | View Object

Alzheimer’s disease is characterized by progressive cognitive decline, accompanied by a loss of neurons and synapses — especially cholinergic synapses — in the basal forebrain, cerebral cortex and hippocampus126 and by a substantial reduction in both muscarinic and nicotinic AChR expression127. PubMed:19721446

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MeSH
Basal Forebrain
MeSH
Cerebral Cortex
MeSH
Hippocampus
Text Location
Review

path(MESH:"Alzheimer Disease") decreases p(HBP:"alpha-4 beta-2 nAChR") View Subject | View Object

in the cerebral cortex, the massive reduction in nAChRs in Alzheimer’s disease128–130 involves predominantly the alpha4beta2 subtype, sparing the alpha7 subtype131. By contrast, in the hippocampus, a loss of alpha7 nAChRs seems to predominate and to correlate with the progressive loss of cognitive function132–136. PubMed:19721446

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MeSH
Cerebral Cortex
Text Location
Review

path(MESH:"Alzheimer Disease") decreases path(MESH:"Memory, Episodic") View Subject | View Object

Similarly, MeM-3454 improved the ‘quality of episodic secondary memory’ score, which is a measure of episodic memory. As for episodic memory, working memory is impaired in Alzheimer’s disease. MeM-3454 significantly improved the quality of working memory score in patients with Alzheimer’s disease in Phase i trials. in a Phase ii trial, the quality of working memory scores were also improved by MeM-3454, as was the ADAS–cog (Alzheimer’s disease assessment scale–cognitive subscale) score. PubMed:19721446

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Review

path(MESH:"Alzheimer Disease") increases path(MESH:"Plaque, Amyloid") View Subject | View Object

Amyloid plaques form in the entorhinal cortex of patients with Alzheimer’s disease and this region, which connects the neocortex and the hippocampus, plays a crucial part in memory. it has been suggested that plaques in this region represent the lytic remnants of degenerated, Abeta1–42-burdened pyramidal neurons, and that amyloid internalization depends on alpha7 nAChR mediated Ca2+ entry162. Of interest, chronic nicotine treatment has been shown to reduce the plaque burden in animal models of Alzheimer’s disease123. PubMed:19721446

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MeSH
Entorhinal Cortex
Text Location
Review

path(MESH:"Alzheimer Disease") negativeCorrelation p(HGNC:CHRNA7) View Subject | View Object

Reduction of α7 AChRs in the CNS is linked with Alzheimer dis- ease, which has been shown to lead to neuronal loss [53,188–190]. PubMed:22040696

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MeSH
Central Nervous System

path(MESH:"Alzheimer Disease") increases bp(GO:"neuron death") View Subject | View Object

Reduction of α7 AChRs in the CNS is linked with Alzheimer dis- ease, which has been shown to lead to neuronal loss [53,188–190]. PubMed:22040696

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MeSH
Central Nervous System

path(MESH:"Alzheimer Disease") decreases bp(GO:memory) View Subject | View Object

One of the salient events at early stages of this disease (usually pre- clinical) is the impairment in hippocampus-based episodic memory which can be improved by enhancement of cholinergic transmission [191]. PubMed:22040696

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MeSH
Hippocampus

path(MESH:"Alzheimer Disease") increases a(HBP:HBP00018) View Subject | View Object

Another important event that associates well with the Alzheimer disease pathology is the aggregation of the β-amyloid peptide [53]. This peptide interacts with α7 AChRs and has been reported to affect the nor- mal functioning of the latter, causing reduced neuronal survival [146,192–194]. PubMed:22040696

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MeSH
Hippocampus

path(MESH:"Alzheimer Disease") association a(HBP:AβOs) View Subject | View Object

a4b2-nAChRs have been implicated in nicotine self-administration, reward, and depen- dence, and in diseases such as Alzheimer’s and epilepsy [1–5,27–33]. PubMed:21787755

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path(MESH:"Alzheimer Disease") association p(MESH:"Receptors, Nicotinic") View Subject | View Object

nAChRs contribute to cognitive function, and changes in their number and/or func- tion are associated with various pathological conditions such as cognitive disorders, anxiety, depression, Alzheimer’s and Parkinson’s disease, pain and epilepsy PubMed:28901280

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path(MESH:"Alzheimer Disease") increases p(MGI:Il6) View Subject | View Object

An elevation of brain IL-6 (Mann–Whitney U=0, Z=-3, p=0.003) and TNF-a (Mann–Whitney U=0, Z=-2.887, p=0.004) was observed in Tg APPsw mice compared to their wild-type littermates (Fig. 9) PubMed:23178521

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MeSH
Brain
MeSH
Alzheimer Disease

path(MESH:"Alzheimer Disease") increases p(MGI:Tnf) View Subject | View Object

An elevation of brain IL-6 (Mann–Whitney U=0, Z=-3, p=0.003) and TNF-a (Mann–Whitney U=0, Z=-2.887, p=0.004) was observed in Tg APPsw mice compared to their wild-type littermates (Fig. 9) PubMed:23178521

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MeSH
Brain
MeSH
Alzheimer Disease

path(MESH:"Alzheimer Disease") increases p(MGI:Stat3, pmod(Ph)) View Subject | View Object

A significant elevation of STAT3 phosphorylation was detected in the brain of Tg APPsw compared to their control littermates (Mann–Whitney U=1, Z=-3.767, p<0.001) and a significant reduction in STAT3 phosphorylation (Mann–Whitney U=8, Z=-2.066, p=0.039) was observed in the brain of Tg APPsw treated with anatabine compared to untreated Tg APPsw littermates (Fig. 10). PubMed:23178521

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MeSH
Brain
MeSH
Alzheimer Disease

path(MESH:"Alzheimer Disease") decreases p(HGNC:TCP1) View Subject | View Object

Four genes that are significantly repressed both in AD and HD (HSP90AB1, HSPA8, HSPA14, and TCP1) are also repressed in aging (Figure 6B). PubMed:25437566

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MeSH
Brain
MeSH
Alzheimer Disease
MeSH
Huntington Disease
MeSH
Parkinson Disease

path(MESH:"Alzheimer Disease") decreases p(HGNC:HSP90AB1) View Subject | View Object

Four genes that are significantly repressed both in AD and HD (HSP90AB1, HSPA8, HSPA14, and TCP1) are also repressed in aging (Figure 6B). PubMed:25437566

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MeSH
Brain
MeSH
Alzheimer Disease
MeSH
Huntington Disease
MeSH
Parkinson Disease

path(MESH:"Alzheimer Disease") decreases p(HGNC:HSPA8) View Subject | View Object

Four genes that are significantly repressed both in AD and HD (HSP90AB1, HSPA8, HSPA14, and TCP1) are also repressed in aging (Figure 6B). PubMed:25437566

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MeSH
Brain
MeSH
Alzheimer Disease
MeSH
Huntington Disease
MeSH
Parkinson Disease

path(MESH:"Alzheimer Disease") decreases p(HGNC:HSPA14) View Subject | View Object

Four genes that are significantly repressed both in AD and HD (HSP90AB1, HSPA8, HSPA14, and TCP1) are also repressed in aging (Figure 6B). PubMed:25437566

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MeSH
Brain
MeSH
Alzheimer Disease
MeSH
Huntington Disease
MeSH
Parkinson Disease

path(MESH:"Alzheimer Disease") positiveCorrelation p(HGNC:MAPT, pmod(Ph, Tyr, 394)) View Subject | View Object

The phosphorylation of tau at Tyr394 and Tyr18 is present in PHFs in the brains of individuals with AD. PubMed:26631930

Appears in Networks:

path(MESH:"Alzheimer Disease") increases path(MESH:Dementia) View Subject | View Object

In AD, the dominant symptom is dementia, initially characterized by a loss of short-term memory which gradually develops into a loss of most higher faculties PubMed:14556719

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path(MESH:"Alzheimer Disease") decreases bp(GO:"short-term memory") View Subject | View Object

In AD, the dominant symptom is dementia, initially characterized by a loss of short-term memory which gradually develops into a loss of most higher faculties PubMed:14556719

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path(MESH:"Alzheimer Disease") increases path(MESH:"Plaque, Amyloid") View Subject | View Object

Patients with AD display two types of protein deposits: extracellular amyloid plaques and intracellular neurofibrillary tangles (Hardy and Selkoe, 2002). PubMed:14556719

Appears in Networks:

path(MESH:"Alzheimer Disease") increases a(MESH:"Neurofibrillary Tangles") View Subject | View Object

Patients with AD display two types of protein deposits: extracellular amyloid plaques and intracellular neurofibrillary tangles (Hardy and Selkoe, 2002). PubMed:14556719

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path(MESH:"Alzheimer Disease") negativeCorrelation act(p(HGNC:UBA1)) View Subject | View Object

Finally, there is also evidence for a reduced activity of E1 and E2 enzymes in cerebral cortex samples from AD patients compared to age-matched controls (Lopez Salon et al., 2000). PubMed:14556719

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MeSH
Cerebral Cortex

path(MESH:"Alzheimer Disease") negativeCorrelation act(p(HGNC:UBA2)) View Subject | View Object

Finally, there is also evidence for a reduced activity of E1 and E2 enzymes in cerebral cortex samples from AD patients compared to age-matched controls (Lopez Salon et al., 2000). PubMed:14556719

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MeSH
Cerebral Cortex

path(MESH:"Alzheimer Disease") negativeCorrelation bp(GO:"proteasome-mediated ubiquitin-dependent protein catabolic process") View Subject | View Object

Taken together, several lines of evidence point to a reduced UPS function in AD and suggest that both Abeta and tau are important players in the game. PubMed:14556719

Appears in Networks:

path(MESH:"Alzheimer Disease") association a(CHEBI:"amyloid-beta") View Subject | View Object

Taken together, several lines of evidence point to a reduced UPS function in AD and suggest that both Abeta and tau are important players in the game. PubMed:14556719

Appears in Networks:

path(MESH:"Alzheimer Disease") association p(HGNC:MAPT) View Subject | View Object

Taken together, several lines of evidence point to a reduced UPS function in AD and suggest that both Abeta and tau are important players in the game. PubMed:14556719

Appears in Networks:

path(MESH:"Alzheimer Disease") decreases p(HGNC:MAPT, pmod(OGlyco)) View Subject | View Object

In AD, the O‑GlcNAcylation of tau is reduced — an effect that might contribute to the hyperphosphorylation and aggregation of tau PubMed:26631930

Appears in Networks:

path(MESH:"Alzheimer Disease") negativeCorrelation act(p(FPLX:Proteasome)) View Subject | View Object

Experiments examining the effects of Aβ on proteasomal activity in vitro revealed an inhibitory effect on the chymotrypsin-like properties of the 20S core (73), consistent with observations of impaired proteasome function in AD patient brains (74). PubMed:25784053

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MeSH
Brain

path(MESH:"Alzheimer Disease") negativeCorrelation bp(GO:macroautophagy) View Subject | View Object

Consistent with a role of autophagy in disease, AD patient tissues exhibit impaired initiation of macroautophagy and an excess of autophagic vacuoles in dystrophic neurites, possibly due to impaired targeting of the vacuolar ATPase to the lysosome (86, 87). PubMed:25784053

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path(MESH:"Alzheimer Disease") positiveCorrelation p(HGNC:MAPT, pmod(Ph)) View Subject | View Object

Thus, we now know three kinases, cdk5, MAP kinase, and GSK-3, all of which are present in neurons, which are capable of transforming tau into the Alzheimer-like state, and therefore could account for the pathological phosphorylation of tau in Alzheimer brains PubMed:8282104

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Confidence
High
MeSH
Neurons

path(MESH:"Alzheimer Disease") positiveCorrelation p(HGNC:CDK5) View Subject | View Object

Thus, we now know three kinases, cdk5, MAP kinase, and GSK-3, all of which are present in neurons, which are capable of transforming tau into the Alzheimer-like state, and therefore could account for the pathological phosphorylation of tau in Alzheimer brains PubMed:8282104

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Confidence
High
MeSH
Neurons

path(MESH:"Alzheimer Disease") positiveCorrelation p(FPLX:ERK) View Subject | View Object

Thus, we now know three kinases, cdk5, MAP kinase, and GSK-3, all of which are present in neurons, which are capable of transforming tau into the Alzheimer-like state, and therefore could account for the pathological phosphorylation of tau in Alzheimer brains PubMed:8282104

Appears in Networks:
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Confidence
High
MeSH
Neurons

path(MESH:"Alzheimer Disease") positiveCorrelation p(FPLX:GSK3) View Subject | View Object

Thus, we now know three kinases, cdk5, MAP kinase, and GSK-3, all of which are present in neurons, which are capable of transforming tau into the Alzheimer-like state, and therefore could account for the pathological phosphorylation of tau in Alzheimer brains PubMed:8282104

Appears in Networks:
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Confidence
High
MeSH
Neurons

path(MESH:"Alzheimer Disease") decreases p(HGNC:SIRT1) View Subject | View Object

Second, while decr1eases in beclin 1 levels in AD remain to be confirmed, SIRT1 expression is diminished 24 . PubMed:30116051

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MeSH
Alzheimer Disease

path(MESH:"Alzheimer Disease") positiveCorrelation g(HGNC:PSEN1, var("?")) View Subject | View Object

Fourth, genetic mutations and anomalies of presenilin 1, a dominant negative gene linked to AD, are associated with reduced lysosomal v-ATPase-mediated acidifica- tion 40,63 , a compromised ALN and deficient mitophagy 64 . PubMed:30116051

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MeSH
Alzheimer Disease

path(MESH:"Alzheimer Disease") negativeCorrelation a(CHEBI:"selenium(2+)") View Subject | View Object

Selenium deficits have been linked to AD, and thus it is interesting that seleno- methionine boosted ALN flux, from AMPK recruit- ment through autophagosome formation to lysosomal degradation, in the 3×Tg AD mouse model 112 . PubMed:30116051

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MeSH
Dopaminergic Neurons

path(MESH:"Alzheimer Disease") increases act(p(HGNC:ABL1)) View Subject | View Object

ABL1 is overactivated in AD and tauopathies such as FTD 152 . PubMed:30116051

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MeSH
Dopaminergic Neurons
MeSH
Machado-Joseph Disease

path(MESH:"Alzheimer Disease") decreases p(HGNC:IDE) View Subject | View Object

Cerebral levels of IDE are reduced in early AD and in mouse models of AD, whereas, mirroring AD amyloidosis, Aβ42 accumulates in mice genetically depleted of IDE. PubMed:30116051

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MeSH
Cerebrum

path(MESH:"Alzheimer Disease") decreases p(HGNC:MME) View Subject | View Object

Similar to IDE, neprilysin catabolizes Aβ42, and its loss in mouse models of AD and in patients with AD alike also contributes to Aβ42 accumulation 253,256,260 . PubMed:30116051

Appears in Networks:

path(MESH:"Alzheimer Disease") increases path(MESH:"Proteostasis Deficiencies") View Subject | View Object

It is well accepted that loss of proteostasis occurs gradually with age and underlies the basis of severe neurodegenerative disorders such as Parkinson’s disease, Huntington’s disease, Alzheimer’s disease, and other types of frontotemporal dementia (Prahlad & Morimoto, 2009; Voisine et al., 2010; Morimoto & Cuervo, 2014) PubMed:29024336

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Confidence
High
MeSH
Brain
MeSH
Neurons

path(MESH:"Alzheimer Disease") positiveCorrelation p(HGNC:MAPT, var("?")) View Subject | View Object

Truncation of Tau by caspases and endopeptidases has been suggested to constitute an important pathogenic step in AD PubMed:29215007

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Confidence
High

path(MESH:"Alzheimer Disease") association p(HGNC:MAPT) View Subject | View Object

Insoluble, fibrillar intraneuronal accumulations of pathological forms of the tau protein called neurofibrillary tangles (NFTs) are important and defining hallmarks of the Alzheimer disease (AD) brain. Indeed, the progression of AD can be neuropathologically staged based on the location and extent of tau pathology (1). PubMed:24027553

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path(MESH:"Alzheimer Disease") association p(HGNC:MAPT) View Subject | View Object

Even though the modifications of tau that are the primary contributors to toxicity have not been conclusively determined, it is clear that tau plays an essential role in the pathogenesis of AD. PubMed:24027553

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path(MESH:"Alzheimer Disease") positiveCorrelation path(MESH:"Neurofibrillary Tangles") View Subject | View Object

Insoluble, fibrillar intraneuronal accumulations of pathological forms of the tau protein called neurofibrillary tangles (NFTs) are important and defining hallmarks of the Alzheimer disease (AD) brain. Indeed, the progression of AD can be neuropathologically staged based on the location and extent of tau pathology (1). PubMed:24027553

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path(MESH:"Alzheimer Disease") association p(HGNC:PIN1) View Subject | View Object

For example, it has been shown that the isomerase Pin1, which has been implicated in AD (30), had opposite effects on P301L and wild-type tau degradation (31). An alternative explanation for the effects of PSA may be that PSA is indirectly regulating tau degradation. PubMed:24027553

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path(MESH:"Alzheimer Disease") increases a(CHEBI:Thrombin, loc(MESH:Microvessels)) View Subject | View Object

A recent study showed that thrombin is elevated in microvessels isolated from AD brain compared to microvessels from control brain (33). Additionally, thrombin was present in the CSF of AD patients but not in that of controls (33). This is important, as thrombin can act as a neurotoxin by activating intracellular signaling cascades causing neurite retraction and stimulating apoptosis (34–36) PubMed:24027553

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Brain
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path(MESH:"Alzheimer Disease") increases a(CHEBI:Thrombin, loc(MESH:"Cerebrospinal Fluid")) View Subject | View Object

A recent study showed that thrombin is elevated in microvessels isolated from AD brain compared to microvessels from control brain (33). Additionally, thrombin was present in the CSF of AD patients but not in that of controls (33). This is important, as thrombin can act as a neurotoxin by activating intracellular signaling cascades causing neurite retraction and stimulating apoptosis (34–36) PubMed:24027553

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path(MESH:"Alzheimer Disease") regulates p(HGNC:MAPT, pmod(Ph)) View Subject | View Object

A final point of interest relates to potential upstream modifications of tau. Endogenous tau is phosphorylated, and in AD, tau phosphorylation becomes dysregulated. This may interfere with subsequent processes including cleavage and degradation. For example, tau that is in the cis-conformation at T231 appears resistant to degradation, as cis-tau is found in dystrophic neurites while trans-tau is not. Additionally cis-tau partitions to the insoluble fraction (30). Phosphorylation at T231 prevents the isomerase Pin1 from converting cis-tau to trans-tau (30). PubMed:24027553

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path(MESH:"Alzheimer Disease") association bp(HBP:"APP processing") View Subject | View Object

Another serine protease recently implicated in tau processing is HTRA1. This is a ubiquitously expressed, ATP-independent intracellular protease. Expression is detectable in many tissues, including the nervous system, although expression is low (40).Nonetheless, this enzyme was initially implicated in AD because it may play a role in amyloid processing (41). PubMed:24027553

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path(MESH:"Alzheimer Disease") increases act(p(HGNC:CAPN2)) View Subject | View Object

The active form of calpain-2 is found in 50–75% of NFTs in tauopathies including AD, but not in protein aggregates found in other diseases (47). This is consistent with another study that found equivalent calpain levels between control and AD cases, but the activity level of the enzyme isolated from AD brain tissue was increased (48). PubMed:24027553

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Alzheimer Disease
MeSH
Tauopathies
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path(MESH:"Alzheimer Disease") positiveCorrelation act(p(HGNC:CASP3)) View Subject | View Object

In order for caspase to cleave tau in the AD brain, it needs to be present in its active form. The active forms of both caspase-3 and caspase-6 are elevated in AD-specific brain regions (temporal and frontal lobes) compared to unaffected regions (cerebellum) and control brains (57, 58). PubMed:24027553

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Frontal Lobe
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Temporal Lobe
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path(MESH:"Alzheimer Disease") positiveCorrelation act(p(HGNC:CASP6)) View Subject | View Object

In order for caspase to cleave tau in the AD brain, it needs to be present in its active form. The active forms of both caspase-3 and caspase-6 are elevated in AD-specific brain regions (temporal and frontal lobes) compared to unaffected regions (cerebellum) and control brains (57, 58). PubMed:24027553

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Frontal Lobe
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Temporal Lobe
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path(MESH:"Alzheimer Disease") positiveCorrelation path(MESH:Inflammation) View Subject | View Object

First, inflammation, which is a common feature of AD, may contribute to tau pathology by activating caspases. Treating cells with the prostaglandin cyclopentenone byproduct PGJ2 increased caspase activity and increased cleaved tau (62). PubMed:24027553

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path(MESH:"Alzheimer Disease") negativeCorrelation bp(GO:"proteasomal protein catabolic process") View Subject | View Object

The accumulation of proteins in AD patients’ brains generated interest in the role of proteasomal function. There is evidence suggesting that proteasomal activity, but not protein level, is decreased in AD-sensitive brain regions specifically compared to unaffected regions (68, 69). PubMed:24027553

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path(MESH:"Alzheimer Disease") increases complex(p(HGNC:MAPT), p(HGNCGENEFAMILY:Proteasome)) View Subject | View Object

Additionally, tau appears to be physically associated with the proteasome in brain tissue from AD cases. When tau was immunoprecipitated it pulled down both the 26S and 20S proteasomes, while immunoprecipitating for the 20S catalytic core pulled down tau (69). PubMed:24027553

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path(MESH:"Alzheimer Disease") positiveCorrelation bp(MESH:Autophagy) View Subject | View Object

This demonstrates that in the absence of mutant PS1, AD-associated impairment in autophagy occurs and thus is due to other factors. Treatment of ex vivo hippocampal slice cultures with lysosomal disruptors causes the formation of enlarged, dystrophic neurites filled with AVs and lysosomes, similar to what is seen in mouse AD models and human AD tissue (85, 86) PubMed:24027553

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path(MESH:"Alzheimer Disease") decreases bp(MESH:Autophagy) View Subject | View Object

However, as previously discussed, autophagy is likely impaired in AD. The tendency for certain phospho-epitopes to show preferential clearance by certain pathways may also relate to their propensity for aggregation. PubMed:24027553

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path(MESH:"Alzheimer Disease") positiveCorrelation a(MESH:Lysosomes) View Subject | View Object

This demonstrates that in the absence of mutant PS1, AD-associated impairment in autophagy occurs and thus is due to other factors. Treatment of ex vivo hippocampal slice cultures with lysosomal disruptors causes the formation of enlarged, dystrophic neurites filled with AVs and lysosomes, similar to what is seen in mouse AD models and human AD tissue (85, 86) PubMed:24027553

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path(MESH:"Alzheimer Disease") positiveCorrelation a(HBP:"3R tau") View Subject | View Object

The band patterns in the immunoblots showed that the AD cases contained a mixture of isoforms, the PiD cases clearly contained 3R isoforms but also some 4R isoforms, while the vast majority of pathology in CBD cases were comprised of 4R tau isoforms PubMed:27574109

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path(MESH:"Alzheimer Disease") positiveCorrelation a(HBP:"4R tau") View Subject | View Object

The band patterns in the immunoblots showed that the AD cases contained a mixture of isoforms, the PiD cases clearly contained 3R isoforms but also some 4R isoforms, while the vast majority of pathology in CBD cases were comprised of 4R tau isoforms PubMed:27574109

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path(MESH:"Alzheimer Disease") positiveCorrelation p(HGNC:MAPT) View Subject | View Object

Total tau levels in the soluble fractions were similar for AD, CBD and PiD, as indicated by the Tau5 sandwich ELISA (Fig. 6B; one-way ANOVA, F(2,9) = 3.283, p = 0.085) PubMed:27574109

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path(MESH:"Alzheimer Disease") positiveCorrelation p(HGNC:MAPT) View Subject | View Object

Total tau levels in the insoluble fractions, as detected by Tau5, were highest in AD, followed by CBD and PiD contained the least (Fig. 6E; one-way ANOVA with Holm-Sidak post-hoc, F(2,9) = 25.93, p = 0.0002) PubMed:27574109

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path(MESH:"Alzheimer Disease") positiveCorrelation a(HBP:"phosphatase-activating domain") View Subject | View Object

In contrast, AD soluble tau displayed the highest level of TNT1 followed by CBD, with PiD having the lowest levels (Fig. 6C; one-way ANOVA with Holm-Sidak post-hoc, F(2,9) = 24.87, p = 0.0002). PubMed:27574109

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path(MESH:"Alzheimer Disease") positiveCorrelation a(HBP:"Tau oligomers") View Subject | View Object

Similarly, the soluble fraction from AD contained the greatest level of TOC1 reactivity, followed by CBD and then PiD had the lowest signal (Fig. 6D; one-way ANOVA with Holm-Sidak post-hoc, F(2,9) = 16.57, p = 0.001) PubMed:27574109

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path(MESH:"Alzheimer Disease") positiveCorrelation a(HBP:"Tau oligomers") View Subject | View Object

TOC1 detected significantly more oligomeric tau in AD compared to CBD and PiD and more in CBD compared to PiD (Fig. 6G; one-way ANOVA with Holm-Sidak post-hoc, F(2,9) = 35.32, p < 0.0001) PubMed:27574109

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path(MESH:"Alzheimer Disease") positiveCorrelation composite(a(HBP:"phosphatase-activating domain"), p(HGNC:MAPT)) View Subject | View Object

TNT1 detected significantly more PAD exposed tau in AD compared to PiD, and more in CBD when compared to PiD, but AD and CBD were not different (Fig. 6F; one-way ANOVA with Holm-Sidak post-hoc, F(2,9) = 12.07, p = 0.0028) PubMed:27574109

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path(MESH:"Alzheimer Disease") positiveCorrelation p(HGNC:MAPT, pmod(Ph, Thr, 231)) View Subject | View Object

Following exposure to ADDLs, double-label immunofluorescence microscopy showed high levels of tau phosphorylated at Thr231, which discriminates among AD and non-AD subjects and patients with other forms of dementia (Hampel et al., 2004, 2003), in neurons with prominent dendritic ADDL binding (detected with NU1, Fig. 2K–M). ADDL binding to synaptic hot-spots in hippocampal neurons is evident in images at highermagnification (60×objective, PanelsLand M). PubMed:17403556

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path(MESH:"Alzheimer Disease") increases p(HGNC:MAPT, pmod(Ph, Thr, 231)) View Subject | View Object

AD brains could induce AD-type tau hyperphosphorylation. Consistent with the results obtained with synthetic ADDLs, we found that treatment of mature hippocampal neuronal cultures with a soluble AD brain extract led to a significant increase in P231 tau phosphorylation (Fig. 6D) compared to cultures treated with a non-AD brain extract (Fig. 6A). PubMed:17403556

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path(MESH:"Alzheimer Disease") positiveCorrelation p(HGNC:MAPT, pmod(HBP:hyperphosphorylation)) View Subject | View Object

AD brains could induce AD-type tau hyperphosphorylation. Consistent with the results obtained with synthetic ADDLs, we found that treatment of mature hippocampal neuronal cultures with a soluble AD brain extract led to a significant increase in P231 tau phosphorylation (Fig. 6D) compared to cultures treated with a non-AD brain extract (Fig. 6A). PubMed:17403556

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path(MESH:"Alzheimer Disease") negativeCorrelation p(HGNCGENEFAMILY:"Ubiquitin conjugating enzymes E2") View Subject | View Object

Interestingly, E1 and E2 enzymes have been reported to be downregulated in AD (de Vrij et al., 2004) (Fig. 2B). PubMed:23528736

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path(MESH:"Alzheimer Disease") association act(p(HBP:"6D tau", frag("2_18"))) View Subject | View Object

These data indicated that increased PAD exposure, as revealed by TNT1 immunoreac- tivity, occurs early in AD and remains present throughout the disease process. PubMed:21734277

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path(MESH:"Alzheimer Disease") association act(p(HBP:"6D tau", frag("2_18"))) View Subject | View Object

Together, these data suggest that increased PAD exposure represents an early event in AD pathogenesis and that AT8 may not be required for PAD ex- posure in situ. PubMed:21734277

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path(MESH:"Alzheimer Disease") positiveCorrelation p(HGNC:UBB) View Subject | View Object

The levels of Ub in AD brain appear to be significantly increased ( Kudo et al., 71 1994 ). PubMed:23528736

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path(MESH:"Alzheimer Disease") positiveCorrelation p(HGNC:UBC) View Subject | View Object

The levels of Ub in AD brain appear to be significantly increased ( Kudo et al., 71 1994 ). PubMed:23528736

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path(MESH:"Alzheimer Disease") positiveCorrelation p(HGNC:UBA52) View Subject | View Object

The levels of Ub in AD brain appear to be significantly increased ( Kudo et al., 71 1994 ). PubMed:23528736

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path(MESH:"Alzheimer Disease") positiveCorrelation p(HGNC:RPS27A) View Subject | View Object

The levels of Ub in AD brain appear to be significantly increased ( Kudo et al., 71 1994 ). PubMed:23528736

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path(MESH:"Alzheimer Disease") positiveCorrelation p(HBP:"UBB+1") View Subject | View Object

A Ub with a 19-residue C-terminal extension from the UBB gene, or UBB+1 (Fig.2A) is selectively expressed in the brains of AD patients (van Leeuwen et al.,1998) and is often found to be accumulated in NFT in Alzheimer’s disease and other tauopathies PubMed:23528736

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Brain

path(MESH:"Alzheimer Disease") negativeCorrelation p(HGNCGENEFAMILY:"Ubiquitin like modifier activating enzymes") View Subject | View Object

Interestingly, E1 and E2 enzymes have been reported to be downregulated in AD (de Vrij et al., 2004) (Fig. 2B). PubMed:23528736

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path(MESH:"Alzheimer Disease") association p(HGNC:UCHL1, var("?")) View Subject | View Object

Mutations in ubiquitin C-terminal hydrolase L1 (UCH-L1) have been proposed to have a role in various neurodegenerative diseases including AD, although the causality of mutations in this gene in Parkinson’s disease is now considered doubtful (Healy et al., 2006; Hutter et al., 2008). PubMed:23528736

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path(MESH:"Alzheimer Disease") decreases bp(MESH:Proteolysis) View Subject | View Object

All three proteolytic activities have been reported to be decreased in AD brains (Keller et al., 2000). PubMed:23528736

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Brain

path(MESH:"Alzheimer Disease") increases a(MESH:Autophagosomes) View Subject | View Object

Pathologically, the AD brains show both accumulated autophagosomes and autolysosomes, suggesting the basal autophagy process in neurons is abnormal in AD (Fig. 3A). PubMed:23528736

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Brain

path(MESH:"Alzheimer Disease") increases a(GO:autolysosome) View Subject | View Object

Pathologically, the AD brains show both accumulated autophagosomes and autolysosomes, suggesting the basal autophagy process in neurons is abnormal in AD (Fig. 3A). PubMed:23528736

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Brain

path(MESH:"Alzheimer Disease") decreases bp(GO:"lysosomal protein catabolic process") View Subject | View Object

The accumulated autophagic vacuoles in AD mainly reflect defected lysosomal clearance instead of induced autophagy. PubMed:23528736

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path(MESH:"Alzheimer Disease") positiveCorrelation p(HGNC:MAPT, pmod(Ph, Ser, 202), pmod(Ph, Thr, 205)) View Subject | View Object

However, this issue is more complicated, as other work has shown that chemical inhibition of Hsp90 by 17-AAG and other inhibitors reduces cellular levels of two phospho- tau species, pS202/T205 and pS396/S404, both of which are relevant to AD pathogenesis [119]. PubMed:21882945

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path(MESH:"Alzheimer Disease") positiveCorrelation p(HGNC:MAPT, pmod(Ph, Ser, 396), pmod(Ph, Ser, 404)) View Subject | View Object

However, this issue is more complicated, as other work has shown that chemical inhibition of Hsp90 by 17-AAG and other inhibitors reduces cellular levels of two phospho- tau species, pS202/T205 and pS396/S404, both of which are relevant to AD pathogenesis [119]. PubMed:21882945

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path(MESH:"Alzheimer Disease") positiveCorrelation p(HGNC:BAG1) View Subject | View Object

BAG1 is upregulated in the hippocampus of AD patients [130], where it associates with tau and increases tau levels in cooperation with Hsp70 [131] PubMed:21882945

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Hippocampus

path(MESH:"Alzheimer Disease") association p(HGNC:MAPT) View Subject | View Object

Tau protein accumulation is the most common pathology among degenerative brain diseases, including Alzheimer’s disease (AD), progressive supranuclear palsy (PSP), traumatic brain injury (TBI) and over twenty others PubMed:30126037

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Confidence
High

path(MESH:"Alzheimer Disease") association bp(MESH:"Cerebrovascular Circulation") View Subject | View Object

Aberrant cerebral blood flow is a functional defect that occurs in AD and tauNFT mice, and is closely associated with cognitive impairment (Wells et al., 2015) PubMed:30126037

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High
MeSH
Neurons

path(MESH:"Alzheimer Disease") increases p(HGNC:AK1) View Subject | View Object

Neuronal expression of AK1 is upregulated in AD patients and is induced by Ab42 PubMed:22419736

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path(MESH:"Alzheimer Disease") increases p(HGNC:AK1) View Subject | View Object

With the immunohisto- chemical analysis, we found that the expression levels of AK1 markedly elevated in the NeuN-positive hippocampal neurons of AD patients PubMed:22419736

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path(MESH:"Alzheimer Disease") increases p(HGNC:MAPT, pmod(Ph, Ser, 396)) View Subject | View Object

Interestingly, the phosphorylated form of tau at Ser 396/404 (PHF-1) was detected exclusively in AD patients, although total amounts of tau protein (TG5) were not changed PubMed:22419736

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path(MESH:"Alzheimer Disease") increases p(HGNC:MAPT, pmod(Ph, Ser, 404)) View Subject | View Object

Interestingly, the phosphorylated form of tau at Ser 396/404 (PHF-1) was detected exclusively in AD patients, although total amounts of tau protein (TG5) were not changed PubMed:22419736

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path(MESH:"Alzheimer Disease") causesNoChange p(HGNC:MAPT) View Subject | View Object

Interestingly, the phosphorylated form of tau at Ser 396/404 (PHF-1) was detected exclusively in AD patients, although total amounts of tau protein (TG5) were not changed PubMed:22419736

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path(MESH:"Alzheimer Disease") decreases p(ECCODE:"2.7.11.31", pmod(Ph, Thr, 172)) View Subject | View Object

Moreover, the phosphorylation of AMPK at Thr172 tended to be reduced in AD patients, although statis- tical significance was marginal PubMed:22419736

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path(MESH:"Alzheimer Disease") increases p(HGNC:FKBP5) View Subject | View Object

However, throughout aging, FKBP51 levels progressively increase and are further increased in AD brain samples (Table 1; Blair et al., 2013; Sabbagh et al., 2014). PubMed:29311797

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path(MESH:"Alzheimer Disease") positiveCorrelation bp(GO:"neuron death") View Subject | View Object

Compared to non-demented controls, AD brains exhibit up to 50% of neuronal loss in the cortex, exceeding the number of NFTs (Gómez-Isla et al., 1997) PubMed:28420982

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Confidence
Medium
MeSH
Cerebral Cortex

path(MESH:"Alzheimer Disease") positiveCorrelation a(GO:"neurofibrillary tangle") View Subject | View Object

Compared to non-demented controls, AD brains exhibit up to 50% of neuronal loss in the cortex, exceeding the number of NFTs (Gómez-Isla et al., 1997) PubMed:28420982

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Confidence
Medium
MeSH
Cerebral Cortex

path(MESH:"Alzheimer Disease") positiveCorrelation a(HBP:"Tau oligomers") View Subject | View Object

The onset of clinical symptoms in AD and PSP brains correlate with elevated levels of tau oligomer (Maeda et al., 2006, 2007; Patterson et al., 2011; Lasagna-Reeves et al., 2012b; Gerson et al., 2014a) PubMed:28420982

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Confidence
Medium
MeSH
Cerebral Cortex

path(MESH:"Alzheimer Disease") positiveCorrelation p(HGNC:MAPT) View Subject | View Object

In AD, the quantity of tau identified in the CSF increases with disease progression (Hampel et al., 2010). However, the mechanism of tau propagation from the brain to the CSF remains elusive PubMed:28420982

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Medium
MeSH
Cerebrospinal Fluid

path(MESH:"Alzheimer Disease") increases p(HGNC:MAPT) View Subject | View Object

In AD, tau pathology has been found to spread from the transentorhinal cortex to the neocortex in a sequential pathway PubMed:28420982

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High
MeSH
Neocortex

path(MESH:"Alzheimer Disease") positiveCorrelation p(HGNC:MAPT) View Subject | View Object

More recently, patients affected with FTD and AD, were found to have high levels of total tau and phosphorylated tau (p-T181 and p-S396; Saman et al., 2012) PubMed:28420982

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Confidence
Medium
MeSH
Cerebrospinal Fluid
MeSH
Alzheimer Disease

path(MESH:"Alzheimer Disease") positiveCorrelation p(HGNC:MAPT, pmod(Ph, Ser, 396)) View Subject | View Object

More recently, patients affected with FTD and AD, were found to have high levels of total tau and phosphorylated tau (p-T181 and p-S396; Saman et al., 2012) PubMed:28420982

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Confidence
Medium
MeSH
Cerebrospinal Fluid
MeSH
Alzheimer Disease

path(MESH:"Alzheimer Disease") positiveCorrelation p(HGNC:MAPT, pmod(Ph, Thr, 181)) View Subject | View Object

More recently, patients affected with FTD and AD, were found to have high levels of total tau and phosphorylated tau (p-T181 and p-S396; Saman et al., 2012) PubMed:28420982

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Confidence
Medium
MeSH
Cerebrospinal Fluid
MeSH
Alzheimer Disease

path(MESH:"Alzheimer Disease") isA path(MESH:Tauopathies) View Subject | View Object

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path(MESH:"Alzheimer Disease") decreases p(HGNC:PPID) View Subject | View Object

An interesting PPIase, CyP40, decreases in aging and is further repressed in AD (Table 1; Brehme et al., 2014). PubMed:29311797

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path(MESH:"Alzheimer Disease") decreases p(HGNC:FKBP4) View Subject | View Object

However, it is interesting to note that FKBP52 levels are lower in the cortex of AD patients’ brains (Table 1; Brehme et al., 2014; Meduri et al., 2016). PubMed:29311797

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MeSH
Cerebral Cortex

path(MESH:"Alzheimer Disease") decreases act(p(HGNC:PPP5C)) View Subject | View Object

PP5 activity has been shown to be repressed in AD (Table 1; Liu et al., 2005). PubMed:29311797

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Cerebral Cortex

path(MESH:"Alzheimer Disease") association p(HGNC:MAPT, pmod(Ph)) View Subject | View Object

Studies have shown that PP5 is able to dephosphorylate tau at several phosphorylation sites connected to AD pathology (Gong et al., 2004). PubMed:29311797

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Cerebral Cortex

path(MESH:"Alzheimer Disease") association p(HGNC:STUB1) View Subject | View Object

CHIP has been linked to several neurodegenerative disorders including Huntington’s disease, Parkinson’s disease and AD as well as other diseases such as cystic fibrosis and cancer (Dickey et al., 2007b; Edkins, 2015). PubMed:29311797

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Cerebral Cortex

path(MESH:"Alzheimer Disease") positiveCorrelation p(HGNC:AHSA1) View Subject | View Object

Aha1 levels have been shown to increase with AD. PubMed:29311797

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Cerebral Cortex

path(MESH:"Alzheimer Disease") positiveCorrelation p(HGNC:MAPT, pmod(Ph, Tyr, 18)) View Subject | View Object

3. Putative phosphorylation sites on tau protein and epitopes specific for major tau antibodies. Red color denotes amino acids phosphorylation in AD brain. PubMed:26751493

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MeSH
Alzheimer Disease

path(MESH:"Alzheimer Disease") positiveCorrelation p(HGNC:MAPT, pmod(Ph, Ser, 68)) View Subject | View Object

3. Putative phosphorylation sites on tau protein and epitopes specific for major tau antibodies. Red color denotes amino acids phosphorylation in AD brain. PubMed:26751493

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MeSH
Alzheimer Disease

path(MESH:"Alzheimer Disease") positiveCorrelation p(HGNC:MAPT, pmod(Ph, Thr, 69)) View Subject | View Object

3. Putative phosphorylation sites on tau protein and epitopes specific for major tau antibodies. Red color denotes amino acids phosphorylation in AD brain. PubMed:26751493

Appears in Networks:
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MeSH
Alzheimer Disease

path(MESH:"Alzheimer Disease") positiveCorrelation p(HGNC:MAPT, pmod(Ph, Thr, 71)) View Subject | View Object

3. Putative phosphorylation sites on tau protein and epitopes specific for major tau antibodies. Red color denotes amino acids phosphorylation in AD brain. PubMed:26751493

Appears in Networks:
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MeSH
Alzheimer Disease

path(MESH:"Alzheimer Disease") positiveCorrelation p(HGNC:MAPT, pmod(Ph, Ser, 113)) View Subject | View Object

3. Putative phosphorylation sites on tau protein and epitopes specific for major tau antibodies. Red color denotes amino acids phosphorylation in AD brain. PubMed:26751493

Appears in Networks:
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MeSH
Alzheimer Disease

path(MESH:"Alzheimer Disease") positiveCorrelation p(HGNC:MAPT, pmod(Ph, Thr, 123)) View Subject | View Object

3. Putative phosphorylation sites on tau protein and epitopes specific for major tau antibodies. Red color denotes amino acids phosphorylation in AD brain. PubMed:26751493

Appears in Networks:
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MeSH
Alzheimer Disease

path(MESH:"Alzheimer Disease") positiveCorrelation p(HGNC:MAPT, pmod(Ph, Thr, 153)) View Subject | View Object

3. Putative phosphorylation sites on tau protein and epitopes specific for major tau antibodies. Red color denotes amino acids phosphorylation in AD brain. PubMed:26751493

Appears in Networks:
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MeSH
Alzheimer Disease

path(MESH:"Alzheimer Disease") positiveCorrelation p(HGNC:MAPT, pmod(Ph, Thr, 175)) View Subject | View Object

3. Putative phosphorylation sites on tau protein and epitopes specific for major tau antibodies. Red color denotes amino acids phosphorylation in AD brain. PubMed:26751493

Appears in Networks:
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MeSH
Alzheimer Disease

path(MESH:"Alzheimer Disease") positiveCorrelation p(HGNC:MAPT, pmod(Ph, Thr, 184)) View Subject | View Object

3. Putative phosphorylation sites on tau protein and epitopes specific for major tau antibodies. Red color denotes amino acids phosphorylation in AD brain. PubMed:26751493

Appears in Networks:
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MeSH
Alzheimer Disease

path(MESH:"Alzheimer Disease") positiveCorrelation p(HGNC:MAPT, pmod(Ph, Ser, 185)) View Subject | View Object

3. Putative phosphorylation sites on tau protein and epitopes specific for major tau antibodies. Red color denotes amino acids phosphorylation in AD brain. PubMed:26751493

Appears in Networks:
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MeSH
Alzheimer Disease

path(MESH:"Alzheimer Disease") positiveCorrelation p(HGNC:MAPT, pmod(Ph, Ser, 191)) View Subject | View Object

3. Putative phosphorylation sites on tau protein and epitopes specific for major tau antibodies. Red color denotes amino acids phosphorylation in AD brain. PubMed:26751493

Appears in Networks:
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MeSH
Alzheimer Disease

path(MESH:"Alzheimer Disease") positiveCorrelation p(HGNC:MAPT, pmod(Ph, Tyr, 197)) View Subject | View Object

3. Putative phosphorylation sites on tau protein and epitopes specific for major tau antibodies. Red color denotes amino acids phosphorylation in AD brain. PubMed:26751493

Appears in Networks:
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MeSH
Alzheimer Disease

path(MESH:"Alzheimer Disease") positiveCorrelation p(HGNC:MAPT, pmod(Ph, Ser, 208)) View Subject | View Object

3. Putative phosphorylation sites on tau protein and epitopes specific for major tau antibodies. Red color denotes amino acids phosphorylation in AD brain. PubMed:26751493

Appears in Networks:
Annotations
MeSH
Alzheimer Disease

path(MESH:"Alzheimer Disease") positiveCorrelation p(HGNC:MAPT, pmod(Ph, Ser, 210)) View Subject | View Object

3. Putative phosphorylation sites on tau protein and epitopes specific for major tau antibodies. Red color denotes amino acids phosphorylation in AD brain. PubMed:26751493

Appears in Networks:
Annotations
MeSH
Alzheimer Disease

path(MESH:"Alzheimer Disease") positiveCorrelation p(HGNC:MAPT, pmod(Ph, Ser, 214)) View Subject | View Object

3. Putative phosphorylation sites on tau protein and epitopes specific for major tau antibodies. Red color denotes amino acids phosphorylation in AD brain. PubMed:26751493

Appears in Networks:
Annotations
MeSH
Alzheimer Disease

path(MESH:"Alzheimer Disease") positiveCorrelation p(HGNC:MAPT, pmod(Ph, Ser, 237)) View Subject | View Object

3. Putative phosphorylation sites on tau protein and epitopes specific for major tau antibodies. Red color denotes amino acids phosphorylation in AD brain. PubMed:26751493

Appears in Networks:
Annotations
MeSH
Alzheimer Disease

path(MESH:"Alzheimer Disease") positiveCorrelation p(HGNC:MAPT, pmod(Ph, Ser, 238)) View Subject | View Object

3. Putative phosphorylation sites on tau protein and epitopes specific for major tau antibodies. Red color denotes amino acids phosphorylation in AD brain. PubMed:26751493

Appears in Networks:
Annotations
MeSH
Alzheimer Disease

path(MESH:"Alzheimer Disease") positiveCorrelation p(HGNC:MAPT, pmod(Ph, Ser, 258)) View Subject | View Object

3. Putative phosphorylation sites on tau protein and epitopes specific for major tau antibodies. Red color denotes amino acids phosphorylation in AD brain. PubMed:26751493

Appears in Networks:
Annotations
MeSH
Alzheimer Disease

path(MESH:"Alzheimer Disease") positiveCorrelation p(HGNC:MAPT, pmod(Ph, Ser, 262)) View Subject | View Object

3. Putative phosphorylation sites on tau protein and epitopes specific for major tau antibodies. Red color denotes amino acids phosphorylation in AD brain. PubMed:26751493

Appears in Networks:
Annotations
MeSH
Alzheimer Disease

path(MESH:"Alzheimer Disease") positiveCorrelation p(HGNC:MAPT, pmod(Ph, Ser, 289)) View Subject | View Object

3. Putative phosphorylation sites on tau protein and epitopes specific for major tau antibodies. Red color denotes amino acids phosphorylation in AD brain. PubMed:26751493

Appears in Networks:
Annotations
MeSH
Alzheimer Disease

path(MESH:"Alzheimer Disease") positiveCorrelation p(HGNC:MAPT, pmod(Ph, Ser, 356)) View Subject | View Object

3. Putative phosphorylation sites on tau protein and epitopes specific for major tau antibodies. Red color denotes amino acids phosphorylation in AD brain. PubMed:26751493

Appears in Networks:
Annotations
MeSH
Alzheimer Disease

path(MESH:"Alzheimer Disease") positiveCorrelation p(HGNC:MAPT, pmod(Ph, Tyr, 394)) View Subject | View Object

3. Putative phosphorylation sites on tau protein and epitopes specific for major tau antibodies. Red color denotes amino acids phosphorylation in AD brain. PubMed:26751493

Appears in Networks:
Annotations
MeSH
Alzheimer Disease

path(MESH:"Alzheimer Disease") positiveCorrelation p(HGNC:MAPT, pmod(Ph, Thr, 403)) View Subject | View Object

3. Putative phosphorylation sites on tau protein and epitopes specific for major tau antibodies. Red color denotes amino acids phosphorylation in AD brain. PubMed:26751493

Appears in Networks:
Annotations
MeSH
Alzheimer Disease

path(MESH:"Alzheimer Disease") positiveCorrelation p(HGNC:MAPT, pmod(Ph, Ser, 409)) View Subject | View Object

3. Putative phosphorylation sites on tau protein and epitopes specific for major tau antibodies. Red color denotes amino acids phosphorylation in AD brain. PubMed:26751493

Appears in Networks:
Annotations
MeSH
Alzheimer Disease

path(MESH:"Alzheimer Disease") positiveCorrelation p(HGNC:MAPT, pmod(Ph, Ser, 435)) View Subject | View Object

3. Putative phosphorylation sites on tau protein and epitopes specific for major tau antibodies. Red color denotes amino acids phosphorylation in AD brain. PubMed:26751493

Appears in Networks:
Annotations
MeSH
Alzheimer Disease

path(MESH:"Alzheimer Disease") positiveCorrelation p(HGNC:MAPT, pmod(Ph, Thr, 427)) View Subject | View Object

3. Putative phosphorylation sites on tau protein and epitopes specific for major tau antibodies. Red color denotes amino acids phosphorylation in AD brain. PubMed:26751493

Appears in Networks:
Annotations
MeSH
Alzheimer Disease

path(MESH:"Alzheimer Disease") positiveCorrelation p(HGNC:MAPT, pmod(Ph, Ser, 433)) View Subject | View Object

3. Putative phosphorylation sites on tau protein and epitopes specific for major tau antibodies. Red color denotes amino acids phosphorylation in AD brain. PubMed:26751493

Appears in Networks:
Annotations
MeSH
Alzheimer Disease

path(MESH:"Alzheimer Disease") positiveCorrelation p(HGNC:MAPT, pmod(Ph, Ser, 422)) View Subject | View Object

3. Putative phosphorylation sites on tau protein and epitopes specific for major tau antibodies. Red color denotes amino acids phosphorylation in AD brain. PubMed:26751493

Appears in Networks:
Annotations
MeSH
Alzheimer Disease

path(MESH:"Alzheimer Disease") positiveCorrelation p(HGNC:MAPT, pmod(Ph)) View Subject | View Object

However, the AD brain extract (3,000g) contained significantly higher levels of phosphorylated tau (Fig. 6h,i,m) when compared with the control brain, especially those associated with some specific phosphorylation sites such as pS199, pS396 and pS404 (Fig. 6i). PubMed:26458742

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Annotations
Confidence
High
MeSH
Brain

path(MESH:"Alzheimer Disease") positiveCorrelation p(HGNC:MAPT, pmod(Ph, Ser, 199)) View Subject | View Object

However, the AD brain extract (3,000g) contained significantly higher levels of phosphorylated tau (Fig. 6h,i,m) when compared with the control brain, especially those associated with some specific phosphorylation sites such as pS199, pS396 and pS404 (Fig. 6i). PubMed:26458742

Appears in Networks:
Annotations
Confidence
High
MeSH
Brain

path(MESH:"Alzheimer Disease") positiveCorrelation p(HGNC:MAPT, pmod(Ph, Ser, 396)) View Subject | View Object

However, the AD brain extract (3,000g) contained significantly higher levels of phosphorylated tau (Fig. 6h,i,m) when compared with the control brain, especially those associated with some specific phosphorylation sites such as pS199, pS396 and pS404 (Fig. 6i). PubMed:26458742

Appears in Networks:
Annotations
Confidence
High
MeSH
Brain

path(MESH:"Alzheimer Disease") positiveCorrelation p(HGNC:MAPT, pmod(Ph, Ser, 404)) View Subject | View Object

However, the AD brain extract (3,000g) contained significantly higher levels of phosphorylated tau (Fig. 6h,i,m) when compared with the control brain, especially those associated with some specific phosphorylation sites such as pS199, pS396 and pS404 (Fig. 6i). PubMed:26458742

Appears in Networks:
Annotations
Confidence
High
MeSH
Brain

path(MESH:"Alzheimer Disease") increases p(HGNC:APP) View Subject | View Object

Emerging evidence suggests that Aβ clearance is impaired in both early-onset and late-onset forms of AD. PubMed:26195256

Appears in Networks:

path(MESH:"Alzheimer Disease") association g(HGNC:PSEN1, var("?")) View Subject | View Object

When characterized by autosomal dominant inheritance, EOAD is related to mutations in the presenilin 1 (PSEN1), presenilin 2 (PSEN2) or amyloid precursor protein (APP) genes. PubMed:26195256

Appears in Networks:

path(MESH:"Alzheimer Disease") association g(HGNC:PSEN2, var("?")) View Subject | View Object

When characterized by autosomal dominant inheritance, EOAD is related to mutations in the presenilin 1 (PSEN1), presenilin 2 (PSEN2) or amyloid precursor protein (APP) genes. PubMed:26195256

Appears in Networks:

path(MESH:"Alzheimer Disease") association g(HGNC:APP, var("?")) View Subject | View Object

When characterized by autosomal dominant inheritance, EOAD is related to mutations in the presenilin 1 (PSEN1), presenilin 2 (PSEN2) or amyloid precursor protein (APP) genes. PubMed:26195256

Appears in Networks:

path(MESH:"Alzheimer Disease") association path(MESH:Aging) View Subject | View Object

Various factors have been reported to positively and negatively modulate the risk of LOAD. Specifically, the greatest overall risk factor for LOAD is ageing; PubMed:26195256

Appears in Networks:

path(MESH:"Alzheimer Disease") association p(HBP:"APOE e4") View Subject | View Object

The strongest identified genetic risk factor for LOAD is the apolipoprotein E (APOE) ε4 allele (APOE*ε4), PubMed:26195256

Appears in Networks:

path(MESH:"Alzheimer Disease") association p(HGNC:TREM2) View Subject | View Object

although genome-wide association studies have linked LOAD to several other genetic variants, such as TREM2 (triggering receptor expressed on myeloid cells 2),27 clusterin (CLU),28 and phosphatidylinositol-binding clathrin assembly protein (PICALM).28,29 PubMed:26195256

Appears in Networks:

path(MESH:"Alzheimer Disease") association p(HGNC:CLU) View Subject | View Object

although genome-wide association studies have linked LOAD to several other genetic variants, such as TREM2 (triggering receptor expressed on myeloid cells 2),27 clusterin (CLU),28 and phosphatidylinositol-binding clathrin assembly protein (PICALM).28,29 PubMed:26195256

Appears in Networks:

path(MESH:"Alzheimer Disease") association p(HGNC:PICALM) View Subject | View Object

although genome-wide association studies have linked LOAD to several other genetic variants, such as TREM2 (triggering receptor expressed on myeloid cells 2),27 clusterin (CLU),28 and phosphatidylinositol-binding clathrin assembly protein (PICALM).28,29 PubMed:26195256

Appears in Networks:

path(MESH:"Alzheimer Disease") association path(MESH:"Cardiovascular Diseases") View Subject | View Object

Known envi- ronmental risk factors for LOAD include cardiovascular disease, and factors conferring a risk of cardiovascu- lar disease, such as diabetes mellitus and hypertension. Head trauma, physical and mental inactivity, and sleep impairment are additional risk factors for LOAD PubMed:26195256

Appears in Networks:

path(MESH:"Alzheimer Disease") association path(MESH:"Diabetes Mellitus") View Subject | View Object

Known envi- ronmental risk factors for LOAD include cardiovascular disease, and factors conferring a risk of cardiovascu- lar disease, such as diabetes mellitus and hypertension. Head trauma, physical and mental inactivity, and sleep impairment are additional risk factors for LOAD PubMed:26195256

Appears in Networks:

path(MESH:"Alzheimer Disease") association path(MESH:Hypertension) View Subject | View Object

Known envi- ronmental risk factors for LOAD include cardiovascular disease, and factors conferring a risk of cardiovascu- lar disease, such as diabetes mellitus and hypertension. Head trauma, physical and mental inactivity, and sleep impairment are additional risk factors for LOAD PubMed:26195256

Appears in Networks:

path(MESH:"Alzheimer Disease") association path(MESH:"Craniocerebral Trauma") View Subject | View Object

Known envi- ronmental risk factors for LOAD include cardiovascular disease, and factors conferring a risk of cardiovascu- lar disease, such as diabetes mellitus and hypertension. Head trauma, physical and mental inactivity, and sleep impairment are additional risk factors for LOAD PubMed:26195256

Appears in Networks:

path(MESH:"Alzheimer Disease") association path(MESH:"Sleep Initiation and Maintenance Disorders") View Subject | View Object

Known envi- ronmental risk factors for LOAD include cardiovascular disease, and factors conferring a risk of cardiovascu- lar disease, such as diabetes mellitus and hypertension. Head trauma, physical and mental inactivity, and sleep impairment are additional risk factors for LOAD PubMed:26195256

Appears in Networks:

path(MESH:"Alzheimer Disease") association path(MESH:"Pick Disease of the Brain") View Subject | View Object

The gross pathological changes consist of brain atrophy, particularly in the hippocampal formation, temporal lobes and parietotemporal cortices, accompanied by cortical thinning, enlarged ventricles and white matter abnormalities, as evident on MRI. PubMed:26195256

Appears in Networks:

path(MESH:"Alzheimer Disease") association a(MESH:"Prefrontal Cortex") View Subject | View Object

The gross pathological changes consist of brain atrophy, particularly in the hippocampal formation, temporal lobes and parietotemporal cortices, accompanied by cortical thinning, enlarged ventricles and white matter abnormalities, as evident on MRI. PubMed:26195256

Appears in Networks:

path(MESH:"Alzheimer Disease") association a(MESH:"Cerebral Cortex") View Subject | View Object

The gross pathological changes consist of brain atrophy, particularly in the hippocampal formation, temporal lobes and parietotemporal cortices, accompanied by cortical thinning, enlarged ventricles and white matter abnormalities, as evident on MRI. PubMed:26195256

Appears in Networks:

path(MESH:"Alzheimer Disease") association a(MESH:"Cerebral Ventricles") View Subject | View Object

The gross pathological changes consist of brain atrophy, particularly in the hippocampal formation, temporal lobes and parietotemporal cortices, accompanied by cortical thinning, enlarged ventricles and white matter abnormalities, as evident on MRI. PubMed:26195256

Appears in Networks:

path(MESH:"Alzheimer Disease") association a(MESH:"White Matter") View Subject | View Object

The gross pathological changes consist of brain atrophy, particularly in the hippocampal formation, temporal lobes and parietotemporal cortices, accompanied by cortical thinning, enlarged ventricles and white matter abnormalities, as evident on MRI. PubMed:26195256

Appears in Networks:

path(MESH:"Alzheimer Disease") decreases bp(GO:"glucose metabolic process") View Subject | View Object

Recent advances now enable several AD-related brain changes to be detected in vivo: 18F-FDG-PET detects decreases in glucose metabolism,45,46 and MRI detects brain atrophy, as well as diffusion and perfu- sion abnormalities, which are most prominent in the vul- nerable hippocampal formation and cortical regions. PubMed:26195256

Appears in Networks:

path(MESH:"Alzheimer Disease") decreases a(MESH:Brain) View Subject | View Object

Recent advances now enable several AD-related brain changes to be detected in vivo: 18F-FDG-PET detects decreases in glucose metabolism,45,46 and MRI detects brain atrophy, as well as diffusion and perfu- sion abnormalities, which are most prominent in the vul- nerable hippocampal formation and cortical regions. PubMed:26195256

Appears in Networks:

path(MESH:"Alzheimer Disease") association a(CHEBI:"amyloid-beta polypeptide 40") View Subject | View Object

Given the size of AD-related proteins, mono- meric Aβ1-40, Aβ1-42 and tau, should be able to pass freely through astrocytic endfeet clefts at the glial barrier.72 PubMed:26195256

Appears in Networks:

path(MESH:"Alzheimer Disease") association a(CHEBI:"amyloid-beta polypeptide 42") View Subject | View Object

Given the size of AD-related proteins, mono- meric Aβ1-40, Aβ1-42 and tau, should be able to pass freely through astrocytic endfeet clefts at the glial barrier.72 PubMed:26195256

Appears in Networks:

path(MESH:"Alzheimer Disease") decreases p(MESH:Neprilysin) View Subject | View Object

First, expression of neprilysin is decreased in AD,126 especially in regions with high Aβ loads such as the hippocampus and temporal gyrus.127 PubMed:26195256

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Annotations
MeSH
Hippocampus
MeSH
Temporal Lobe

path(MESH:"Alzheimer Disease") increases p(HGNC:MMP2) View Subject | View Object

Although overall matrix metallo- proteinase 2 expression is increased in AD,58 its activity is reduced in astrocytes that surround Aβ plaques. PubMed:26195256

Appears in Networks:
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MeSH
Hippocampus
MeSH
Temporal Lobe

path(MESH:"Alzheimer Disease") decreases p(HGNC:LRP1) View Subject | View Object

In AD, these factors are impaired in a number of ways. First, expression of the blood efflux transporters LRP1123 and ABCB1147 is decreased, whereas expression of the blood influx transporter RAGE is upregulated. PubMed:26195256

Appears in Networks:
Annotations
MeSH
Hippocampus
MeSH
Temporal Lobe

path(MESH:"Alzheimer Disease") decreases p(HGNC:ABCB1) View Subject | View Object

In AD, these factors are impaired in a number of ways. First, expression of the blood efflux transporters LRP1123 and ABCB1147 is decreased, whereas expression of the blood influx transporter RAGE is upregulated. PubMed:26195256

Appears in Networks:
Annotations
MeSH
Hippocampus
MeSH
Temporal Lobe

path(MESH:"Alzheimer Disease") increases p(HGNC:AGER) View Subject | View Object

In AD, these factors are impaired in a number of ways. First, expression of the blood efflux transporters LRP1123 and ABCB1147 is decreased, whereas expression of the blood influx transporter RAGE is upregulated. PubMed:26195256

Appears in Networks:
Annotations
MeSH
Hippocampus
MeSH
Temporal Lobe

path(MESH:"Alzheimer Disease") increases path(MESH:"Calcification, Physiologic") View Subject | View Object

In AD, the choroid plexus undergoes many structural changes, such as calcification, fibrosis and Aβ deposition, all of which can obstruct CSF production. PubMed:26195256

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MeSH
Choroid Plexus

path(MESH:"Alzheimer Disease") increases path(MESH:Fibrosis) View Subject | View Object

In AD, the choroid plexus undergoes many structural changes, such as calcification, fibrosis and Aβ deposition, all of which can obstruct CSF production. PubMed:26195256

Appears in Networks:
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MeSH
Choroid Plexus

path(MESH:"Alzheimer Disease") positiveCorrelation p(HGNC:MAPT, pmod(Ph)) View Subject | View Object

The amount of total tau captured with pS422 (detected with the pan-tau antibody, Tau5) was significantly higher in AD compared to control (Fig. 7E; t10 = 6.07, p = 0.0001). The level of pS422 tau that also contained PAD exposed tau (i.e., TNT1 reactive) was significantly higher in AD compared to control (Fig. 7F; t10 = 2.31, p = 0.0435). Similarly, the level of pS422 tau that also contained an oligomeric conformation (i.e., TOC1 reactive) was significantly higher in AD compared to control (Fig. 7G; t10 = 1.51, p = 0.0029). PubMed:27373205

Appears in Networks:

path(MESH:"Alzheimer Disease") positiveCorrelation a(HBP:"Tau aggregates") View Subject | View Object

The amount of total tau captured with pS422 (detected with the pan-tau antibody, Tau5) was significantly higher in AD compared to control (Fig. 7E; t10 = 6.07, p = 0.0001). The level of pS422 tau that also contained PAD exposed tau (i.e., TNT1 reactive) was significantly higher in AD compared to control (Fig. 7F; t10 = 2.31, p = 0.0435). Similarly, the level of pS422 tau that also contained an oligomeric conformation (i.e., TOC1 reactive) was significantly higher in AD compared to control (Fig. 7G; t10 = 1.51, p = 0.0029). PubMed:27373205

Appears in Networks:

path(MESH:"Alzheimer Disease") positiveCorrelation a(HBP:"amyloid-beta aggregates") View Subject | View Object

AD (Alzheimer’s disease) is a progressive neurodegenerative disorder characterized by the extracellular accumulation of amyloid beta-peptide and the intracellular accumulation of tau PubMed:22817713

Appears in Networks:
Annotations
Confidence
Medium
MeSH
Extracellular Space

path(MESH:"Alzheimer Disease") positiveCorrelation a(HBP:"Tau aggregates") View Subject | View Object

AD (Alzheimer’s disease) is a progressive neurodegenerative disorder characterized by the extracellular accumulation of amyloid beta-peptide and the intracellular accumulation of tau PubMed:22817713

Appears in Networks:
Annotations
Confidence
Medium
MeSH
Intracellular Space

path(MESH:"Alzheimer Disease") positiveCorrelation path(MESH:"Plaque, Amyloid") View Subject | View Object

AD (Alzheimer’s disease) is a progressive neurodegenerative disorder characterized by the extracellular accumulation of senile plaques composed of Aβ (amyloid β-peptide) and the intracellular accumulation of the MAP (microtubuleassociated protein) tau into both non-filamentous and filamentous inclusions, such as NFTs (neurofibrillary tangles), NTs (neuropil threads) and NPs (neuritic plaques) [1,2] PubMed:22817713

Appears in Networks:
Annotations
Confidence
Medium
MeSH
Extracellular Space

path(MESH:"Alzheimer Disease") association a(GO:"neurofibrillary tangle") View Subject | View Object

AD (Alzheimer’s disease) is a progressive neurodegenerative disorder characterized by the extracellular accumulation of senile plaques composed of Aβ (amyloid β-peptide) and the intracellular accumulation of the MAP (microtubuleassociated protein) tau into both non-filamentous and filamentous inclusions, such as NFTs (neurofibrillary tangles), NTs (neuropil threads) and NPs (neuritic plaques) [1,2] PubMed:22817713

Appears in Networks:
Annotations
Confidence
Medium
MeSH
Intracellular Space

path(MESH:"Alzheimer Disease") association a(MESH:"Neuropil Threads") View Subject | View Object

AD (Alzheimer’s disease) is a progressive neurodegenerative disorder characterized by the extracellular accumulation of senile plaques composed of Aβ (amyloid β-peptide) and the intracellular accumulation of the MAP (microtubuleassociated protein) tau into both non-filamentous and filamentous inclusions, such as NFTs (neurofibrillary tangles), NTs (neuropil threads) and NPs (neuritic plaques) [1,2] PubMed:22817713

Appears in Networks:
Annotations
Confidence
Medium
MeSH
Intracellular Space

path(MESH:"Alzheimer Disease") increases p(HGNC:MAPT, pmod(Ph)) View Subject | View Object

The tau protein becomes highly phosphorylated in AD and this is likely to induce a conformational change causing its detachment from microtubules and its accumulation in aggregates [3] PubMed:22817713

Appears in Networks:
Annotations
Confidence
High
MeSH
Intracellular Space

path(MESH:"Alzheimer Disease") increases a(HBP:"Tau oligomers") View Subject | View Object

TOC1’s immunoreactivity is greatly elevated in AD brains compared with healthy controls, but co-localizes best with early-stage markers for AD pathogenesis such as pS422 [16] PubMed:22817713

Appears in Networks:
Annotations
Confidence
Medium
MeSH
Intracellular Space

path(MESH:"Alzheimer Disease") decreases bp(GO:"proteasome-mediated ubiquitin-dependent protein catabolic process") View Subject | View Object

However, their dysfunction in AD due to some factors will reduce Aβ clearance PubMed:29626319

Appears in Networks:

path(MESH:"Alzheimer Disease") decreases bp(GO:"lysosomal microautophagy") View Subject | View Object

However, their dysfunction in AD due to some factors will reduce Aβ clearance PubMed:29626319

Appears in Networks:

path(MESH:"Alzheimer Disease") decreases deg(a(CHEBI:"amyloid-beta")) View Subject | View Object

However, their dysfunction in AD due to some factors will reduce Aβ clearance PubMed:29626319

Appears in Networks:

path(MESH:"Alzheimer Disease") increases a(CHEBI:"amyloid-beta") View Subject | View Object

However, recently, it has been reported that the expression and transport activity of P-gp are impaired in sporadic AD as a result of its ubiquitination, internalization, and proteasome-dependent degradation derived from Aβ40 (Chiu et al. 2015; Hartz et al. 2016), which will result in Aβ deposition PubMed:29626319

Appears in Networks:

path(MESH:"Alzheimer Disease") positiveCorrelation act(p(HGNC:ACE)) View Subject | View Object

In addition, ACE expression also enhances Aβ clearance, and the levels and activity of ACE are elevated in AD brains (Barnes et al. 1991; Hemming and Selkoe 2005) PubMed:29626319

Appears in Networks:

path(MESH:"Alzheimer Disease") negativeCorrelation p(HGNC:SERPINF2) View Subject | View Object

However, the levels and activity of plasmin are reduced in AD brains (Ledesma et al. 2000) PubMed:29626319

Appears in Networks:

path(MESH:"Alzheimer Disease") negativeCorrelation act(p(HGNC:SERPINF2)) View Subject | View Object

However, the levels and activity of plasmin are reduced in AD brains (Ledesma et al. 2000) PubMed:29626319

Appears in Networks:

path(MESH:"Alzheimer Disease") negativeCorrelation p(HGNC:PICALM) View Subject | View Object

And in AD, the decreasing expression of PICALM in brain endothelium reduces Aβ clearance (Zhao et al. 2015b) PubMed:29626319

Appears in Networks:
Annotations
MeSH
Alzheimer Disease

path(MESH:"Alzheimer Disease") decreases p(HGNC:ABCB1) View Subject | View Object

However, recently, it has been reported that the expression and transport activity of P-gp are impaired in sporadic AD as a result of its ubiquitination, internalization, and proteasome-dependent degradation derived from Aβ40 (Chiu et al. 2015; Hartz et al. 2016), which will result in Aβ deposition PubMed:29626319

Appears in Networks:

path(MESH:"Alzheimer Disease") decreases tloc(a(CHEBI:water), fromLoc(GO:"extracellular region"), toLoc(MESH:"Cerebrospinal Fluid")) View Subject | View Object

In a similar manner, a recent experiment indicated that water influx into the CSF is significantly reduced in AD-patients, which may impair Aβ clearance (Suzuki et al. 2015) PubMed:29626319

Appears in Networks:

path(MESH:"Alzheimer Disease") negativeCorrelation p(HGNC:PICALM) View Subject | View Object

Phosphatidylinositol binding clathrin assembly protein, PICALM (aka CALM) assembles adaptor protein-2 (AP-2) to clathrin, thus participating in clathrin-mediated endocytosis. We have previously reported that the level of full-length PICALM is decreased in AD brains; PICALM was co-localised with phosphorylated tau in NFTs and in granulovacuolar degenerations (GVDs) in the brains of AD patients and of individuals with Down syndrome but was not observed in amyloid plaques (Ando et al., 2013). PubMed:27260836

Appears in Networks:
Annotations
Disease Ontology (DO)
Alzheimer's disease
Disease Ontology (DO)
Down syndrome

path(MESH:"Alzheimer Disease") negativeCorrelation act(p(HGNC:SIRT1)) View Subject | View Object

SIRT1 activation or elevation ameliorates pathology and neurodegeneration in AD (Qin et al., 2006; Kim et al., 2007). Loss of SIRT1 induces impairment of learning and memory (Gao et al., 2010; Michán et al., 2010). PubMed:29540553

Appears in Networks:

path(MESH:"Alzheimer Disease") positiveCorrelation p(HGNC:MAPT, var("p.Asp13*")) View Subject | View Object

While several N and C-terminally truncated Tau species are observed in AD brains, only a limited number of specific Tau cleavage sites, after residues Asp13, Asp25, Asn368, Glu391 and Asp421, have been identified so far in situ. The species generated by these cleavages are found in neurofibrillary tangles, and their occurrence is correlated with the severity of the disease. PubMed:25974414

Appears in Networks:
Annotations
Disease Ontology (DO)
Alzheimer's disease

path(MESH:"Alzheimer Disease") positiveCorrelation p(HGNC:MAPT, var("p.Asp25*")) View Subject | View Object

While several N and C-terminally truncated Tau species are observed in AD brains, only a limited number of specific Tau cleavage sites, after residues Asp13, Asp25, Asn368, Glu391 and Asp421, have been identified so far in situ. The species generated by these cleavages are found in neurofibrillary tangles, and their occurrence is correlated with the severity of the disease. PubMed:25974414

Appears in Networks:
Annotations
Disease Ontology (DO)
Alzheimer's disease

path(MESH:"Alzheimer Disease") positiveCorrelation p(HGNC:MAPT, var("p.Asp368*")) View Subject | View Object

While several N and C-terminally truncated Tau species are observed in AD brains, only a limited number of specific Tau cleavage sites, after residues Asp13, Asp25, Asn368, Glu391 and Asp421, have been identified so far in situ. The species generated by these cleavages are found in neurofibrillary tangles, and their occurrence is correlated with the severity of the disease. PubMed:25974414

Appears in Networks:
Annotations
Disease Ontology (DO)
Alzheimer's disease

path(MESH:"Alzheimer Disease") positiveCorrelation p(HGNC:MAPT, var("p.Glu391*")) View Subject | View Object

While several N and C-terminally truncated Tau species are observed in AD brains, only a limited number of specific Tau cleavage sites, after residues Asp13, Asp25, Asn368, Glu391 and Asp421, have been identified so far in situ. The species generated by these cleavages are found in neurofibrillary tangles, and their occurrence is correlated with the severity of the disease. PubMed:25974414

Appears in Networks:
Annotations
Disease Ontology (DO)
Alzheimer's disease

path(MESH:"Alzheimer Disease") positiveCorrelation p(HGNC:MAPT, var("p.Asp421*")) View Subject | View Object

While several N and C-terminally truncated Tau species are observed in AD brains, only a limited number of specific Tau cleavage sites, after residues Asp13, Asp25, Asn368, Glu391 and Asp421, have been identified so far in situ. The species generated by these cleavages are found in neurofibrillary tangles, and their occurrence is correlated with the severity of the disease. PubMed:25974414

Appears in Networks:
Annotations
Disease Ontology (DO)
Alzheimer's disease

path(MESH:"Alzheimer Disease") positiveCorrelation act(a(CHEBI:acrolein)) View Subject | View Object

We were prompted to carry out this study because Acr is mainly localized in the neurons [54], is found in association with NFTs and dystrophic neurites surrounding senile plaques [55], is highly toxic to neurons, is found elevated 2–5 fold in affected regions of AD brain. EC can sequester highly reactive and toxic byproducts of oxidation such as acrolein. PubMed:23531502

Appears in Networks:

path(MESH:"Alzheimer Disease") negativeCorrelation bp(GO:"canonical glycolysis") View Subject | View Object

Triosephosphate isomerase (TPI) is a key enzyme in cell metabolism that controls the glycolytic flow and energy production through the interconversion of dihydroxyacetone phosphate (DHAP) and D-glyceraldehyde 3-phosphate (G3P) (Richard, 1993). Notably, TPI is the only glycolytic enzyme whose functional deficiency is associated to neurodegeneration (Eber et al., 1991; Ovadi et al., 2004). In particular, inefficient glycolysis (Hoyer et al., 1988) and ATP depletion (Keil et al., 2004) are characteristic in Alzheimer’s disease brains. PubMed:19251756

Appears in Networks:

path(MESH:"Alzheimer Disease") positiveCorrelation p(INTERPRO:"Triosephosphate isomerase", pmod(NO, Tyr, 164)) View Subject | View Object

Ab induced nitro-oxidative stress on human neuroblastoma cells, resulting in nitrotyrosination of TPI. Moreover, higher levels of nitro-TPI were also detected in extracts from hippocampus (Fig. 1F) and frontal cortex (Fig. 1G) obtained from Alzheimer’s disease brains, compared with healthy subjects. PubMed:19251756

Appears in Networks:
Annotations
Uberon
frontal cortex
Uberon
hippocampal formation
Disease Ontology (DO)
Alzheimer's disease

path(MESH:"Alzheimer Disease") positiveCorrelation p(INTERPRO:"Triosephosphate isomerase", pmod(NO, Tyr, 208)) View Subject | View Object

Ab induced nitro-oxidative stress on human neuroblastoma cells, resulting in nitrotyrosination of TPI. Moreover, higher levels of nitro-TPI were also detected in extracts from hippocampus (Fig. 1F) and frontal cortex (Fig. 1G) obtained from Alzheimer’s disease brains, compared with healthy subjects. PubMed:19251756

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Uberon
frontal cortex
Uberon
hippocampal formation
Disease Ontology (DO)
Alzheimer's disease

path(MESH:"Alzheimer Disease") positiveCorrelation act(p(ECCODE:"2.3.2.13")) View Subject | View Object

The number of neurons that are immunoreactive with an antibody directed at the epsilon-(gamma-glutamyl)lysine bond was significantly higher in AD cortex compared with age-matched controls and schizophrenics. PHF tau-directed antibodies AT8, MC-1 and PHF-1 co-localized with epsilon(gamma-glutamyl)lysine immunolabeling in AD NFT. Immunoaffinity purification and immunoblotting experiments demonstrated that PHF tau contains epsilon(gamma-glutamyl)lysine bonds in parietal and frontal cortex in AD. In control cases with NFT present in the entorhinal cortex and hippocampus, indicative of Braak and Braak stage II, epsilon(gamma-glutamyl)lysine bonds were present in PHF tau in parietal and frontal cortex, despite the lack of microscopically detectable NFT or senile plaques in these cortical regions. The presence of PHF tau with epsilon(gamma-glutamyl)lysine bonds in brain regions devoid of NFT in stage II (but regions, which would be expected to contain NFT in stage III) suggests that these bonds occur early in the formation of NFT. PubMed:11738469

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Uberon
frontal cortex
Uberon
parietal cortex
Disease Ontology (DO)
Alzheimer's disease

path(MESH:"Alzheimer Disease") positiveCorrelation act(p(ECCODE:"2.3.2.13")) View Subject | View Object

Degenerating neurons from the AD hippocampus, compared to neurons from the normal aged hippocampus, exhibited increased immunoreactivity for TGase and demonstrated co-labeling for PHF1 and anti-TGase. Our results suggest that TGase may be associated with the neurofibrillary degeneration observed in AD, thereby implicating TGase as a potential factor in the pathogenesis of Alzheimer's disease. PubMed:8985134

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Uberon
hippocampal formation
Disease Ontology (DO)
Alzheimer's disease

path(MESH:"Alzheimer Disease") increases act(p(HGNC:TGM2)) View Subject | View Object

Total transglutaminase activity was significantly higher in the Alzheimer's disease prefrontal cortex compared to control. In addition the levels of tissue transglutaminase, as determined by quantitative immunoblotting, were elevated approximately 3-fold in Alzheimer's disease prefrontal cortex compared to control. To our knowledge, this is the first demonstration that transglutaminase is increased in Alzheimer's disease brain. There were no significant differences in transglutaminase activity or levels in the cerebellum between control and Alzheimer's disease cases. Because the elevation of transglutaminase in the Alzheimer's disease samples occurred in the prefrontal cortex, where neurofibrillary pathology is usually abundant, and not in the cerebellum, which is usually spared in Alzheimer's disease, it can be suggested that transglutaminase could be a contributing factor in neurofibrillary tangle formation. PubMed:9099822

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Uberon
prefrontal cortex
Disease Ontology (DO)
Alzheimer's disease

path(MESH:"Alzheimer Disease") positiveCorrelation p(HGNC:MAPT, pmod(HBP:nitration, Tyr, 29)) View Subject | View Object

Tau-nY29 detects soluble tau and paired helical filament tau from severely affected Alzheimer's brain but fails to recognize tau from normal aged brain. This observation suggests that nitration at Tyr29 is a disease-related event that may alter the intrinsic ability of tau to self-polymerize. In Alzheimer's brain, Tau-nY29 labels the fibrillar triad of tau lesions, including neurofibrillary tangles, neuritic plaques, and, to a lesser extent, neuropil threads. Intriguingly, although Tau-nY29 stains both the neuronal and glial tau pathology of Pick disease, it detects only the neuronal pathology in corticobasal degeneration and progressive supranuclear palsy without labeling the predominant glial pathology. PubMed:17050703

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Disease Ontology (DO)
Alzheimer's disease

path(MESH:"Alzheimer Disease") association g(DBSNP:rs2651206) View Subject | View Object

Haplotype analysis of the block formed by rs2651206, rs10807287, and rs7764257 showed that the combination of the three frequent alleles (CTA) was significantly (p = 0.02) overrepresented in the AD group (67%) compared to the control group (63%), and this result was still significant after multiple testing corrections with 10,000 permutations (p = 0.05). PubMed:20096481

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path(MESH:"Alzheimer Disease") positiveCorrelation g(DBSNP:rs2651206) View Subject | View Object

Significant association with a reduced risk of LOAD (odds ratio/OR=0.69). rs2651206 polymorphism was strongly associated with LOAD (OR=0.72) (age, gender, and APOE adjusted). The TG haplotype, deriving from the two minor alleles, decreases risk of LOAD (OR=0.78, P=0.037). PubMed:21548880

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path(MESH:"Alzheimer Disease") association g(DBSNP:rs10807287) View Subject | View Object

Haplotype analysis of the block formed by rs2651206, rs10807287, and rs7764257 showed that the combination of the three frequent alleles (CTA) was significantly (p = 0.02) overrepresented in the AD group (67%) compared to the control group (63%), and this result was still significant after multiple testing corrections with 10,000 permutations (p = 0.05). PubMed:20096481

Appears in Networks:

path(MESH:"Alzheimer Disease") association g(DBSNP:rs7764257) View Subject | View Object

Haplotype analysis of the block formed by rs2651206, rs10807287, and rs7764257 showed that the combination of the three frequent alleles (CTA) was significantly (p = 0.02) overrepresented in the AD group (67%) compared to the control group (63%), and this result was still significant after multiple testing corrections with 10,000 permutations (p = 0.05). PubMed:20096481

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path(MESH:"Alzheimer Disease") positiveCorrelation p(HGNC:MARK4) View Subject | View Object

In cells, a CagA peptide inhibited tau phosphorylation at Ser²6² mediated by MARK4 but not other MARK isoforms. A strong and significant elevation of MARK4 expression and MARK4-tau interactions in AD brains correlated with the Braak stages of the disease. PubMed:23666762

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path(MESH:"Alzheimer Disease") positiveCorrelation p(HBP:"CDK5R1 p25") View Subject | View Object

To perform its function, Cdk5 must bind to the neuron-specific regulatory subunit protein p35, which is beneficial for neuronal development (Tsai et al. 1994; Chae et al. 1997). However, truncation of p35 and conversion to p25 (Patrick et al. 1999) is found in the forebrain of rats after focal cerebral ischemia and in AD patients, and these alterations are deleterious to the brain PubMed:26118667

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path(MESH:"Alzheimer Disease") positiveCorrelation p(HGNC:MAPT, pmod(Ph, Thr, 231)) View Subject | View Object

This sequence (Fig. 3G–N) is supported by Western blot analysis, phosphorylated Thr231 in three AD cases and their age-matched controls, suggesting that tau phosphorylation at Thr231 occurs before the formation of oligomers (Fig. 3O). PubMed:22253473

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MeSH
Alzheimer Disease

path(MESH:"Alzheimer Disease") increases p(HGNC:MAPK1) View Subject | View Object

The highly vulnerable CA1 pyramidal neurons were characterized by age- and disease-unrelated increases in PRCKB levels and by age- and disease-related increases in MAPK1 levels. In contrast, low PRKCB levels were found in CA2 pyramidal neurons, and MAPK1 levels were elevated in controls and intermediate AD stages. Both PRKCB and MAPK1 were increased in the late AD stages. MAPK1 and PRKCB levels were low in the brainstem and cerebellum. PubMed:21910444

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Uberon
pyramidal layer of CA1
MeSH
Alzheimer Disease

path(MESH:"Alzheimer Disease") increases p(HGNC:PRKCB) View Subject | View Object

The highly vulnerable CA1 pyramidal neurons were characterized by age- and disease-unrelated increases in PRCKB levels and by age- and disease-related increases in MAPK1 levels. In contrast, low PRKCB levels were found in CA2 pyramidal neurons, and MAPK1 levels were elevated in controls and intermediate AD stages. Both PRKCB and MAPK1 were increased in the late AD stages. MAPK1 and PRKCB levels were low in the brainstem and cerebellum. PubMed:21910444

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Uberon
pyramidal layer of CA1
MeSH
Alzheimer Disease

path(MESH:"Alzheimer Disease") increases p(HGNC:ITPKB) View Subject | View Object

We show here that ITPKB protein level was increased 3-fold in the cerebral cortex of most patients with Alzheimer's disease compared with control subjects, and accumulated in dystrophic neurites associated to amyloid plaques. In mouse Neuro-2a neuroblastoma cells, Itpkb overexpression was associated with increased cell apoptosis and increased β-secretase 1 activity leading to overproduction of amyloid-β peptides. In this cellular model, an inhibitor of mitogen-activated kinase kinases 1/2 completely prevented overproduction of amyloid-β peptides. Transgenic overexpression of ITPKB in mouse forebrain neurons was not sufficient to induce amyloid plaque formation or tau hyperphosphorylation. However, in the 5X familial Alzheimer's disease mouse model, neuronal ITPKB overexpression significantly increased extracellular signal-regulated kinases 1/2 activation and β-secretase 1 activity, resulting in exacerbated Alzheimer's disease pathology as shown by increased astrogliosis, amyloid-β40 peptide production and tau hyperphosphorylation. PubMed:24401760

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Uberon
cerebral cortex
MeSH
Alzheimer Disease

path(MESH:"Alzheimer Disease") negativeCorrelation p(MGI:Sirt1) View Subject | View Object

Here we show that the protein deacetylase SIRT1 reduces tau acetylation in a mouse model of neurodegeneration. SIRT1 deficiency in the brain aggravates synapse loss and behavioral disinhibition, and SIRT1 overexpression ameliorates propagation of tau pathology. PubMed:29540553

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path(MESH:"Alzheimer Disease") negativeCorrelation p(MGI:Sirt3) View Subject | View Object

Sirt3 levels were reduced in the entorhinal cortex, the middle temporal gyrus, and the superior frontal gyrus of AD subjects compared to those of CN and was associated with poorer test scores of neuropsychological evaluation and the severity of tau pathology. PubMed:29540553

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Uberon
entorhinal cortex
Uberon
middle temporal gyrus
Uberon
superior frontal gyrus

path(MESH:"Alzheimer Disease") positiveCorrelation p(HGNC:MAPT, pmod(Ac, Lys, 280)) View Subject | View Object

We also tested for ac-tau 280 in early stage Alzheimer's disease (Braak stage 1). Histopathological examination using the ac tau 280 antibody was performed in three Alzheimer's cases and three CTE patients. Presence of ac-tau 280 was confirmed in all cases at early sites of disease manifestation. These findings suggest that tau acetylation may precede tau phosphorylation and could be the first PubMed:29276758

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MeSH
Alzheimer Disease

path(MESH:"Alzheimer Disease") positiveCorrelation p(HGNC:MAPT, pmod(Ac, Lys, 280)) View Subject | View Object

Thus, K280 acetylation is a feature found in a variety of human 4R or 3R/4R tauopathies including AD, but not 3R-tauopathies such as PiD. PubMed:21427723

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path(MESH:"Alzheimer Disease") isA path(HBP:"4R tauopathy") View Subject | View Object

Appears in Networks:

path(MESH:"Alzheimer Disease") negativeCorrelation a(HBP:"O-GlcNAcylation") View Subject | View Object

This post-translational modification is likely an indicator of good health since its intracellular level correlates with the availability of extracellular glucose. From a more practical point of view, it has been shown that O-GlcNAcylation impairments contribute to the etiology of cardiovascular diseases, type-2 diabetes and Alzheimer's disease (AD), three illnesses common in occidental societies. PubMed:19732809

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path(MESH:"Alzheimer Disease") positiveCorrelation p(HGNC:SUMO1) View Subject | View Object

The plasma level of SUMO1 was significantly increased in dementia patients, as compared to control groups. The levels of SUMO1 correlated to decreased Mini-Mental State Examination (r =-0.123, p = 0.029). These results suggest that elevated plasma SUMO1 levels may be associated with AD. PubMed:27716675

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path(MESH:"Alzheimer Disease") positiveCorrelation g(DBSNP:rs761059) View Subject | View Object

The genotype distribution of a polymorphism in intron 7 (rs761059) differed between AD cases and controls, with an adjusted odds ratio (OR) of 1.45 (p=0.046, 95% CI: 1.01-2.08). One haplotype (ht2 CAGAG) was found in 14.0% of the AD patients and in 11.1% of the controls (p=0.04, OR=1.43. 95% CI; 1.01-2.01). Stratification by the ApoE gave no significant difference between the groups but when stratified by gender, two SNPs (rs8052688, rs8063) were significantly associated with the risk of MCI among women. PubMed:19765634

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path(MESH:"Alzheimer Disease") decreases p(HGNC:LCMT1) View Subject | View Object

Western blot analyses showed a decrease of methyl-PP2A and an increase of demethyl-PP2A with a concomitant reduction in the methyl/demethyl PP2A ratio in both PSP (74%) and AD (76%) brains, associated with an LCMT-1 decrease and a demethylating enzyme increase, protein phosphatase methylesterase (PME-1), in both diseases. PubMed:29281045

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path(MESH:"Alzheimer Disease") increases p(ECCODE:"3.1.1.89") View Subject | View Object

Western blot analyses showed a decrease of methyl-PP2A and an increase of demethyl-PP2A with a concomitant reduction in the methyl/demethyl PP2A ratio in both PSP (74%) and AD (76%) brains, associated with an LCMT-1 decrease and a demethylating enzyme increase, protein phosphatase methylesterase (PME-1), in both diseases. PubMed:29281045

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path(MESH:"Alzheimer Disease") negativeCorrelation p(HBP:"cis p-tau") View Subject | View Object

Pin1 accelerates cis to trans conversion to prevent accumulation of pathogenic cis p-tau conformation in AD, providing the first structural evidence for how Pin1 protects against AD. PubMed:23157676

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path(MESH:"Alzheimer Disease") positiveCorrelation p(HGNC:IL1B) View Subject | View Object

Interleukins, in particular IL-1β and IL-18, are upregulated in AD brain, and the overexpression of IL-1β or IL-18 is critical for the onset of the inflammatory process (Rubio-Perez and Morillas-Ruiz, 2012), and both mediate the expression of a vast array of inflammatory genes (Weber et al., 2010) PubMed:24561250

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Confidence
High
NeuroMMSigDB
Inflammatory response subgraph
NeuroMMSigDB
Interleukin signaling subgraph

path(MESH:"Alzheimer Disease") positiveCorrelation p(HGNC:IL18) View Subject | View Object

Interleukins, in particular IL-1β and IL-18, are upregulated in AD brain, and the overexpression of IL-1β or IL-18 is critical for the onset of the inflammatory process (Rubio-Perez and Morillas-Ruiz, 2012), and both mediate the expression of a vast array of inflammatory genes (Weber et al., 2010) PubMed:24561250

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Annotations
Confidence
High
NeuroMMSigDB
Inflammatory response subgraph
NeuroMMSigDB
Interleukin signaling subgraph

path(MESH:"Alzheimer Disease") association complex(GO:"NLRP3 inflammasome complex") View Subject | View Object

In support, a recent study in APP/PS1 mice confirms that the NLRP3 inflammasome contributes to the AD pathology (Heneka et al., 2013) PubMed:24561250

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Confidence
Medium

path(MESH:"Alzheimer Disease") positiveCorrelation bp(GO:aging) View Subject | View Object

Aging, another risk factor of AD, has been found to activate the NLRP1 inflammasome and upregulate IL-18 and IL-1β levels in the hippocampus of aged mice (Mawhinney et al., 2011) PubMed:24561250

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Confidence
Medium
MeSH
Hippocampus
NeuroMMSigDB
Interleukin signaling subgraph

path(MESH:"Alzheimer Disease") positiveCorrelation p(HGNC:PYCARD) View Subject | View Object

In addition, NLRC4 and ASC levels are upregulated in the brains of AD patients (Liu and Chan, 2014), suggesting a possible role of the NLRC4 inflammasome in AD pathogenesis PubMed:24561250

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Annotations
Confidence
Medium
NeuroMMSigDB
Caspase subgraph

path(MESH:"Alzheimer Disease") positiveCorrelation p(HGNC:NLRC4) View Subject | View Object

In addition, NLRC4 and ASC levels are upregulated in the brains of AD patients (Liu and Chan, 2014), suggesting a possible role of the NLRC4 inflammasome in AD pathogenesis PubMed:24561250

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Annotations
Confidence
Medium
NeuroMMSigDB
Caspase subgraph

path(MESH:"Alzheimer Disease") association complex(GO:"IPAF inflammasome complex") View Subject | View Object

In addition, NLRC4 and ASC levels are upregulated in the brains of AD patients (Liu and Chan, 2014), suggesting a possible role of the NLRC4 inflammasome in AD pathogenesis PubMed:24561250

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Annotations
Confidence
Medium
NeuroMMSigDB
Caspase subgraph

path(MESH:"Alzheimer Disease") association complex(GO:"inflammasome complex") View Subject | View Object

They appear to be involved in several pathological processes activated by microbes including Alzheimer’s disease (AD). PubMed:27314526

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Confidence
High

path(MESH:"Alzheimer Disease") positiveCorrelation p(HGNC:P2RX7) View Subject | View Object

P2X7 expressed by microglial cells will also activate the NLP3 inflammasome [30, 32] and the expression of P2X7 is likely to be increased in AD brains [35]. PubMed:27314526

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Confidence
Medium
MeSH
Alzheimer Disease
NeuroMMSigDB
Caspase subgraph

path(MESH:"Alzheimer Disease") positiveCorrelation p(HGNC:IL1B) View Subject | View Object

Increased levels of IL-1 beta and IL-18 have been detected in serum, cerebrospinal fluid, and brains of patients with AD and in other forms of dementia [42–46]. PubMed:27314526

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Annotations
Confidence
High
MeSH
Brain
MeSH
Cerebrospinal Fluid
MeSH
Serum
MeSH
Alzheimer Disease
NeuroMMSigDB
Interleukin signaling subgraph

path(MESH:"Alzheimer Disease") positiveCorrelation p(HGNC:IL18) View Subject | View Object

Increased levels of IL-1 beta and IL-18 have been detected in serum, cerebrospinal fluid, and brains of patients with AD and in other forms of dementia [42–46]. PubMed:27314526

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Annotations
Confidence
High
MeSH
Brain
MeSH
Cerebrospinal Fluid
MeSH
Serum
MeSH
Alzheimer Disease
NeuroMMSigDB
Interleukin signaling subgraph

path(MESH:"Alzheimer Disease") association p(HGNC:IL18) View Subject | View Object

Both these studies indicated an important role of IL-18 in AD. PubMed:27314526

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Annotations
Confidence
High
MeSH
Alzheimer Disease
NeuroMMSigDB
Interleukin signaling subgraph

path(MESH:"Alzheimer Disease") positiveCorrelation p(HGNC:HSD17B10) View Subject | View Object

Binding of Aβ to ABAD has been implicated in the development of AD, recent studies detected elevated ABAD levels in the regions of the hippocampus and cerebral cortex which are generally affected by AD pathology PubMed:30444369

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MeSH
Cerebral Cortex
MeSH
Hippocampus

path(MESH:"Alzheimer Disease") negativeCorrelation act(p(HGNC:PRDX2)) View Subject | View Object

The first, peroxiredoxin-2 (Prdx-2), functions as an antioxidant and has been shown to be inactivated in AD. PubMed:30444369

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MeSH
Neurons

path(MESH:"Alzheimer Disease") positiveCorrelation p(HGNC:PRDX2) View Subject | View Object

In transgenic AD mice and the post-mortem human brain of AD patients, the expression of Prdx-2 is shown to be elevated, due to the attempted protection of neurons from Aβ-induced toxicity. PubMed:30444369

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MeSH
Neurons

path(MESH:"Alzheimer Disease") positiveCorrelation p(HGNC:CDK5) View Subject | View Object

Inactivation of Prdx-2 is controlled by a kinase that has been shown to be elevated in AD, CDK5, 107, 108 which phosphorylates Thr 89 and results in deactivation of Prdx-2. PubMed:30444369

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MeSH
Neurons

path(MESH:"Alzheimer Disease") positiveCorrelation p(HGNC:SH3GL2) View Subject | View Object

The second ABAD-related protein, endophilin-1 (Ep-1), is a member of a family of proteins that are responsible for synaptic vesicle endocytosis, mitochondrial function, and receptor trafficking. 110 This family of proteins has been implicated in a number of neurodegenerative diseases, 111 including in AD where it is overexpressed PubMed:30444369

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MeSH
Neurons

path(MESH:"Alzheimer Disease") positiveCorrelation a(HBP:"protein aggregates") View Subject | View Object

Overexpression of the HSPB8-BAG3 complex also stimulates autophagy and facilitates the clearance of mutated aggregation-prone proteins, the accumulation of which characterizes many neurodegenerative disorders such as Alzheimer disease, Parkinson disease, and amyotrophic lateral sclerosis (Seidel et al., 2011). PubMed:22020111

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path(MESH:"Alzheimer Disease") increases p(HGNC:AGRN) View Subject | View Object

In Alzheimer disease, 66 genes were identified that are also modulated by Protandim at the gene expression level. Of these 66 genes, the first 43 of them (65%) were regulated by Protandim in the opposing direction to that taken by the Alzheimer disease process. The beneficial effect of Protandim is further supported by the fact that of the 10 gene products currently targeted by drug therapies, eight of them are modulated by Protandim in the same direction that is proposed to be beneficial and caused by the drug. PubMed:22020111

Appears in Networks:

path(MESH:"Alzheimer Disease") increases p(HGNC:ANP32A) View Subject | View Object

In Alzheimer disease, 66 genes were identified that are also modulated by Protandim at the gene expression level. Of these 66 genes, the first 43 of them (65%) were regulated by Protandim in the opposing direction to that taken by the Alzheimer disease process. The beneficial effect of Protandim is further supported by the fact that of the 10 gene products currently targeted by drug therapies, eight of them are modulated by Protandim in the same direction that is proposed to be beneficial and caused by the drug. PubMed:22020111

Appears in Networks:

path(MESH:"Alzheimer Disease") increases p(HGNC:BAX) View Subject | View Object

In Alzheimer disease, 66 genes were identified that are also modulated by Protandim at the gene expression level. Of these 66 genes, the first 43 of them (65%) were regulated by Protandim in the opposing direction to that taken by the Alzheimer disease process. The beneficial effect of Protandim is further supported by the fact that of the 10 gene products currently targeted by drug therapies, eight of them are modulated by Protandim in the same direction that is proposed to be beneficial and caused by the drug. PubMed:22020111

Appears in Networks:

path(MESH:"Alzheimer Disease") increases p(HGNC:BCHE) View Subject | View Object

In Alzheimer disease, 66 genes were identified that are also modulated by Protandim at the gene expression level. Of these 66 genes, the first 43 of them (65%) were regulated by Protandim in the opposing direction to that taken by the Alzheimer disease process. The beneficial effect of Protandim is further supported by the fact that of the 10 gene products currently targeted by drug therapies, eight of them are modulated by Protandim in the same direction that is proposed to be beneficial and caused by the drug. PubMed:22020111

Appears in Networks:

path(MESH:"Alzheimer Disease") increases p(HGNC:BGN) View Subject | View Object

In Alzheimer disease, 66 genes were identified that are also modulated by Protandim at the gene expression level. Of these 66 genes, the first 43 of them (65%) were regulated by Protandim in the opposing direction to that taken by the Alzheimer disease process. The beneficial effect of Protandim is further supported by the fact that of the 10 gene products currently targeted by drug therapies, eight of them are modulated by Protandim in the same direction that is proposed to be beneficial and caused by the drug. PubMed:22020111

Appears in Networks:

path(MESH:"Alzheimer Disease") increases p(HGNC:BRCA1) View Subject | View Object

In Alzheimer disease, 66 genes were identified that are also modulated by Protandim at the gene expression level. Of these 66 genes, the first 43 of them (65%) were regulated by Protandim in the opposing direction to that taken by the Alzheimer disease process. The beneficial effect of Protandim is further supported by the fact that of the 10 gene products currently targeted by drug therapies, eight of them are modulated by Protandim in the same direction that is proposed to be beneficial and caused by the drug. PubMed:22020111

Appears in Networks:

path(MESH:"Alzheimer Disease") increases p(HGNC:CADPS2) View Subject | View Object

In Alzheimer disease, 66 genes were identified that are also modulated by Protandim at the gene expression level. Of these 66 genes, the first 43 of them (65%) were regulated by Protandim in the opposing direction to that taken by the Alzheimer disease process. The beneficial effect of Protandim is further supported by the fact that of the 10 gene products currently targeted by drug therapies, eight of them are modulated by Protandim in the same direction that is proposed to be beneficial and caused by the drug. PubMed:22020111

Appears in Networks:

path(MESH:"Alzheimer Disease") increases p(HGNC:CAPN1) View Subject | View Object

In Alzheimer disease, 66 genes were identified that are also modulated by Protandim at the gene expression level. Of these 66 genes, the first 43 of them (65%) were regulated by Protandim in the opposing direction to that taken by the Alzheimer disease process. The beneficial effect of Protandim is further supported by the fact that of the 10 gene products currently targeted by drug therapies, eight of them are modulated by Protandim in the same direction that is proposed to be beneficial and caused by the drug. PubMed:22020111

Appears in Networks:

path(MESH:"Alzheimer Disease") increases p(HGNC:CCNB1) View Subject | View Object

In Alzheimer disease, 66 genes were identified that are also modulated by Protandim at the gene expression level. Of these 66 genes, the first 43 of them (65%) were regulated by Protandim in the opposing direction to that taken by the Alzheimer disease process. The beneficial effect of Protandim is further supported by the fact that of the 10 gene products currently targeted by drug therapies, eight of them are modulated by Protandim in the same direction that is proposed to be beneficial and caused by the drug. PubMed:22020111

Appears in Networks:

path(MESH:"Alzheimer Disease") increases p(HGNC:CDK1) View Subject | View Object

In Alzheimer disease, 66 genes were identified that are also modulated by Protandim at the gene expression level. Of these 66 genes, the first 43 of them (65%) were regulated by Protandim in the opposing direction to that taken by the Alzheimer disease process. The beneficial effect of Protandim is further supported by the fact that of the 10 gene products currently targeted by drug therapies, eight of them are modulated by Protandim in the same direction that is proposed to be beneficial and caused by the drug. PubMed:22020111

Appears in Networks:

path(MESH:"Alzheimer Disease") increases p(HGNC:CDK2) View Subject | View Object

In Alzheimer disease, 66 genes were identified that are also modulated by Protandim at the gene expression level. Of these 66 genes, the first 43 of them (65%) were regulated by Protandim in the opposing direction to that taken by the Alzheimer disease process. The beneficial effect of Protandim is further supported by the fact that of the 10 gene products currently targeted by drug therapies, eight of them are modulated by Protandim in the same direction that is proposed to be beneficial and caused by the drug. PubMed:22020111

Appears in Networks:

path(MESH:"Alzheimer Disease") increases p(HGNC:CDKN2A) View Subject | View Object

In Alzheimer disease, 66 genes were identified that are also modulated by Protandim at the gene expression level. Of these 66 genes, the first 43 of them (65%) were regulated by Protandim in the opposing direction to that taken by the Alzheimer disease process. The beneficial effect of Protandim is further supported by the fact that of the 10 gene products currently targeted by drug therapies, eight of them are modulated by Protandim in the same direction that is proposed to be beneficial and caused by the drug. PubMed:22020111

Appears in Networks:

path(MESH:"Alzheimer Disease") increases p(HGNC:CXCR4) View Subject | View Object

In Alzheimer disease, 66 genes were identified that are also modulated by Protandim at the gene expression level. Of these 66 genes, the first 43 of them (65%) were regulated by Protandim in the opposing direction to that taken by the Alzheimer disease process. The beneficial effect of Protandim is further supported by the fact that of the 10 gene products currently targeted by drug therapies, eight of them are modulated by Protandim in the same direction that is proposed to be beneficial and caused by the drug. PubMed:22020111

Appears in Networks:

path(MESH:"Alzheimer Disease") increases p(HGNC:EIF4EBP1) View Subject | View Object

In Alzheimer disease, 66 genes were identified that are also modulated by Protandim at the gene expression level. Of these 66 genes, the first 43 of them (65%) were regulated by Protandim in the opposing direction to that taken by the Alzheimer disease process. The beneficial effect of Protandim is further supported by the fact that of the 10 gene products currently targeted by drug therapies, eight of them are modulated by Protandim in the same direction that is proposed to be beneficial and caused by the drug. PubMed:22020111

Appears in Networks:

path(MESH:"Alzheimer Disease") increases p(HGNC:FOLH1) View Subject | View Object

In Alzheimer disease, 66 genes were identified that are also modulated by Protandim at the gene expression level. Of these 66 genes, the first 43 of them (65%) were regulated by Protandim in the opposing direction to that taken by the Alzheimer disease process. The beneficial effect of Protandim is further supported by the fact that of the 10 gene products currently targeted by drug therapies, eight of them are modulated by Protandim in the same direction that is proposed to be beneficial and caused by the drug. PubMed:22020111

Appears in Networks:

path(MESH:"Alzheimer Disease") increases p(HGNC:HOMER1) View Subject | View Object

In Alzheimer disease, 66 genes were identified that are also modulated by Protandim at the gene expression level. Of these 66 genes, the first 43 of them (65%) were regulated by Protandim in the opposing direction to that taken by the Alzheimer disease process. The beneficial effect of Protandim is further supported by the fact that of the 10 gene products currently targeted by drug therapies, eight of them are modulated by Protandim in the same direction that is proposed to be beneficial and caused by the drug. PubMed:22020111

Appears in Networks:

path(MESH:"Alzheimer Disease") increases p(HGNC:HRH1) View Subject | View Object

In Alzheimer disease, 66 genes were identified that are also modulated by Protandim at the gene expression level. Of these 66 genes, the first 43 of them (65%) were regulated by Protandim in the opposing direction to that taken by the Alzheimer disease process. The beneficial effect of Protandim is further supported by the fact that of the 10 gene products currently targeted by drug therapies, eight of them are modulated by Protandim in the same direction that is proposed to be beneficial and caused by the drug. PubMed:22020111

Appears in Networks:

path(MESH:"Alzheimer Disease") increases p(HGNC:IGF2) View Subject | View Object

In Alzheimer disease, 66 genes were identified that are also modulated by Protandim at the gene expression level. Of these 66 genes, the first 43 of them (65%) were regulated by Protandim in the opposing direction to that taken by the Alzheimer disease process. The beneficial effect of Protandim is further supported by the fact that of the 10 gene products currently targeted by drug therapies, eight of them are modulated by Protandim in the same direction that is proposed to be beneficial and caused by the drug. PubMed:22020111

Appears in Networks:

path(MESH:"Alzheimer Disease") increases p(HGNC:IGFBP2) View Subject | View Object

In Alzheimer disease, 66 genes were identified that are also modulated by Protandim at the gene expression level. Of these 66 genes, the first 43 of them (65%) were regulated by Protandim in the opposing direction to that taken by the Alzheimer disease process. The beneficial effect of Protandim is further supported by the fact that of the 10 gene products currently targeted by drug therapies, eight of them are modulated by Protandim in the same direction that is proposed to be beneficial and caused by the drug. PubMed:22020111

Appears in Networks:

path(MESH:"Alzheimer Disease") increases p(HGNC:LDLR) View Subject | View Object

In Alzheimer disease, 66 genes were identified that are also modulated by Protandim at the gene expression level. Of these 66 genes, the first 43 of them (65%) were regulated by Protandim in the opposing direction to that taken by the Alzheimer disease process. The beneficial effect of Protandim is further supported by the fact that of the 10 gene products currently targeted by drug therapies, eight of them are modulated by Protandim in the same direction that is proposed to be beneficial and caused by the drug. PubMed:22020111

Appears in Networks:

path(MESH:"Alzheimer Disease") increases p(HGNC:MAOA) View Subject | View Object

In Alzheimer disease, 66 genes were identified that are also modulated by Protandim at the gene expression level. Of these 66 genes, the first 43 of them (65%) were regulated by Protandim in the opposing direction to that taken by the Alzheimer disease process. The beneficial effect of Protandim is further supported by the fact that of the 10 gene products currently targeted by drug therapies, eight of them are modulated by Protandim in the same direction that is proposed to be beneficial and caused by the drug. PubMed:22020111

Appears in Networks:

path(MESH:"Alzheimer Disease") increases p(HGNC:NEFH) View Subject | View Object

In Alzheimer disease, 66 genes were identified that are also modulated by Protandim at the gene expression level. Of these 66 genes, the first 43 of them (65%) were regulated by Protandim in the opposing direction to that taken by the Alzheimer disease process. The beneficial effect of Protandim is further supported by the fact that of the 10 gene products currently targeted by drug therapies, eight of them are modulated by Protandim in the same direction that is proposed to be beneficial and caused by the drug. PubMed:22020111

Appears in Networks:

path(MESH:"Alzheimer Disease") increases p(HGNC:NPDC1) View Subject | View Object

In Alzheimer disease, 66 genes were identified that are also modulated by Protandim at the gene expression level. Of these 66 genes, the first 43 of them (65%) were regulated by Protandim in the opposing direction to that taken by the Alzheimer disease process. The beneficial effect of Protandim is further supported by the fact that of the 10 gene products currently targeted by drug therapies, eight of them are modulated by Protandim in the same direction that is proposed to be beneficial and caused by the drug. PubMed:22020111

Appears in Networks:

path(MESH:"Alzheimer Disease") increases p(HGNC:NRGN) View Subject | View Object

In Alzheimer disease, 66 genes were identified that are also modulated by Protandim at the gene expression level. Of these 66 genes, the first 43 of them (65%) were regulated by Protandim in the opposing direction to that taken by the Alzheimer disease process. The beneficial effect of Protandim is further supported by the fact that of the 10 gene products currently targeted by drug therapies, eight of them are modulated by Protandim in the same direction that is proposed to be beneficial and caused by the drug. PubMed:22020111

Appears in Networks:

path(MESH:"Alzheimer Disease") increases p(HGNC:PREP) View Subject | View Object

In Alzheimer disease, 66 genes were identified that are also modulated by Protandim at the gene expression level. Of these 66 genes, the first 43 of them (65%) were regulated by Protandim in the opposing direction to that taken by the Alzheimer disease process. The beneficial effect of Protandim is further supported by the fact that of the 10 gene products currently targeted by drug therapies, eight of them are modulated by Protandim in the same direction that is proposed to be beneficial and caused by the drug. PubMed:22020111

Appears in Networks:

path(MESH:"Alzheimer Disease") increases p(HGNC:PROS1) View Subject | View Object

In Alzheimer disease, 66 genes were identified that are also modulated by Protandim at the gene expression level. Of these 66 genes, the first 43 of them (65%) were regulated by Protandim in the opposing direction to that taken by the Alzheimer disease process. The beneficial effect of Protandim is further supported by the fact that of the 10 gene products currently targeted by drug therapies, eight of them are modulated by Protandim in the same direction that is proposed to be beneficial and caused by the drug. PubMed:22020111

Appears in Networks:

path(MESH:"Alzheimer Disease") increases p(HGNC:PTGS1) View Subject | View Object

In Alzheimer disease, 66 genes were identified that are also modulated by Protandim at the gene expression level. Of these 66 genes, the first 43 of them (65%) were regulated by Protandim in the opposing direction to that taken by the Alzheimer disease process. The beneficial effect of Protandim is further supported by the fact that of the 10 gene products currently targeted by drug therapies, eight of them are modulated by Protandim in the same direction that is proposed to be beneficial and caused by the drug. PubMed:22020111

Appears in Networks:

path(MESH:"Alzheimer Disease") increases p(HGNC:SELENBP1) View Subject | View Object

In Alzheimer disease, 66 genes were identified that are also modulated by Protandim at the gene expression level. Of these 66 genes, the first 43 of them (65%) were regulated by Protandim in the opposing direction to that taken by the Alzheimer disease process. The beneficial effect of Protandim is further supported by the fact that of the 10 gene products currently targeted by drug therapies, eight of them are modulated by Protandim in the same direction that is proposed to be beneficial and caused by the drug. PubMed:22020111

Appears in Networks:

path(MESH:"Alzheimer Disease") increases p(HGNC:TAGLN) View Subject | View Object

In Alzheimer disease, 66 genes were identified that are also modulated by Protandim at the gene expression level. Of these 66 genes, the first 43 of them (65%) were regulated by Protandim in the opposing direction to that taken by the Alzheimer disease process. The beneficial effect of Protandim is further supported by the fact that of the 10 gene products currently targeted by drug therapies, eight of them are modulated by Protandim in the same direction that is proposed to be beneficial and caused by the drug. PubMed:22020111

Appears in Networks:

path(MESH:"Alzheimer Disease") increases p(HGNC:TGFB1) View Subject | View Object

In Alzheimer disease, 66 genes were identified that are also modulated by Protandim at the gene expression level. Of these 66 genes, the first 43 of them (65%) were regulated by Protandim in the opposing direction to that taken by the Alzheimer disease process. The beneficial effect of Protandim is further supported by the fact that of the 10 gene products currently targeted by drug therapies, eight of them are modulated by Protandim in the same direction that is proposed to be beneficial and caused by the drug. PubMed:22020111

Appears in Networks:

path(MESH:"Alzheimer Disease") increases p(HGNC:TUBB3) View Subject | View Object

In Alzheimer disease, 66 genes were identified that are also modulated by Protandim at the gene expression level. Of these 66 genes, the first 43 of them (65%) were regulated by Protandim in the opposing direction to that taken by the Alzheimer disease process. The beneficial effect of Protandim is further supported by the fact that of the 10 gene products currently targeted by drug therapies, eight of them are modulated by Protandim in the same direction that is proposed to be beneficial and caused by the drug. PubMed:22020111

Appears in Networks:

path(MESH:"Alzheimer Disease") increases p(HGNC:VKORC1) View Subject | View Object

In Alzheimer disease, 66 genes were identified that are also modulated by Protandim at the gene expression level. Of these 66 genes, the first 43 of them (65%) were regulated by Protandim in the opposing direction to that taken by the Alzheimer disease process. The beneficial effect of Protandim is further supported by the fact that of the 10 gene products currently targeted by drug therapies, eight of them are modulated by Protandim in the same direction that is proposed to be beneficial and caused by the drug. PubMed:22020111

Appears in Networks:

path(MESH:"Alzheimer Disease") decreases p(HGNC:CANX) View Subject | View Object

In Alzheimer disease, 66 genes were identified that are also modulated by Protandim at the gene expression level. Of these 66 genes, the first 43 of them (65%) were regulated by Protandim in the opposing direction to that taken by the Alzheimer disease process. The beneficial effect of Protandim is further supported by the fact that of the 10 gene products currently targeted by drug therapies, eight of them are modulated by Protandim in the same direction that is proposed to be beneficial and caused by the drug. PubMed:22020111

Appears in Networks:

path(MESH:"Alzheimer Disease") decreases p(HGNC:GCNT2) View Subject | View Object

In Alzheimer disease, 66 genes were identified that are also modulated by Protandim at the gene expression level. Of these 66 genes, the first 43 of them (65%) were regulated by Protandim in the opposing direction to that taken by the Alzheimer disease process. The beneficial effect of Protandim is further supported by the fact that of the 10 gene products currently targeted by drug therapies, eight of them are modulated by Protandim in the same direction that is proposed to be beneficial and caused by the drug. PubMed:22020111

Appears in Networks:

path(MESH:"Alzheimer Disease") decreases p(HGNC:IDE) View Subject | View Object

In Alzheimer disease, 66 genes were identified that are also modulated by Protandim at the gene expression level. Of these 66 genes, the first 43 of them (65%) were regulated by Protandim in the opposing direction to that taken by the Alzheimer disease process. The beneficial effect of Protandim is further supported by the fact that of the 10 gene products currently targeted by drug therapies, eight of them are modulated by Protandim in the same direction that is proposed to be beneficial and caused by the drug. PubMed:22020111

Appears in Networks:

path(MESH:"Alzheimer Disease") decreases p(HGNC:MMP1) View Subject | View Object

In Alzheimer disease, 66 genes were identified that are also modulated by Protandim at the gene expression level. Of these 66 genes, the first 43 of them (65%) were regulated by Protandim in the opposing direction to that taken by the Alzheimer disease process. The beneficial effect of Protandim is further supported by the fact that of the 10 gene products currently targeted by drug therapies, eight of them are modulated by Protandim in the same direction that is proposed to be beneficial and caused by the drug. PubMed:22020111

Appears in Networks:

path(MESH:"Alzheimer Disease") decreases p(HGNC:NFE2L2) View Subject | View Object

In Alzheimer disease, 66 genes were identified that are also modulated by Protandim at the gene expression level. Of these 66 genes, the first 43 of them (65%) were regulated by Protandim in the opposing direction to that taken by the Alzheimer disease process. The beneficial effect of Protandim is further supported by the fact that of the 10 gene products currently targeted by drug therapies, eight of them are modulated by Protandim in the same direction that is proposed to be beneficial and caused by the drug. PubMed:22020111

Appears in Networks:

path(MESH:"Alzheimer Disease") decreases p(HGNC:NR3C1) View Subject | View Object

In Alzheimer disease, 66 genes were identified that are also modulated by Protandim at the gene expression level. Of these 66 genes, the first 43 of them (65%) were regulated by Protandim in the opposing direction to that taken by the Alzheimer disease process. The beneficial effect of Protandim is further supported by the fact that of the 10 gene products currently targeted by drug therapies, eight of them are modulated by Protandim in the same direction that is proposed to be beneficial and caused by the drug. PubMed:22020111

Appears in Networks:

path(MESH:"Alzheimer Disease") decreases p(HGNC:PPARA) View Subject | View Object

In Alzheimer disease, 66 genes were identified that are also modulated by Protandim at the gene expression level. Of these 66 genes, the first 43 of them (65%) were regulated by Protandim in the opposing direction to that taken by the Alzheimer disease process. The beneficial effect of Protandim is further supported by the fact that of the 10 gene products currently targeted by drug therapies, eight of them are modulated by Protandim in the same direction that is proposed to be beneficial and caused by the drug. PubMed:22020111

Appears in Networks:

path(MESH:"Alzheimer Disease") decreases p(HGNC:SLC6A6) View Subject | View Object

In Alzheimer disease, 66 genes were identified that are also modulated by Protandim at the gene expression level. Of these 66 genes, the first 43 of them (65%) were regulated by Protandim in the opposing direction to that taken by the Alzheimer disease process. The beneficial effect of Protandim is further supported by the fact that of the 10 gene products currently targeted by drug therapies, eight of them are modulated by Protandim in the same direction that is proposed to be beneficial and caused by the drug. PubMed:22020111

Appears in Networks:

path(MESH:"Alzheimer Disease") decreases p(HGNC:SYVN1) View Subject | View Object

In Alzheimer disease, 66 genes were identified that are also modulated by Protandim at the gene expression level. Of these 66 genes, the first 43 of them (65%) were regulated by Protandim in the opposing direction to that taken by the Alzheimer disease process. The beneficial effect of Protandim is further supported by the fact that of the 10 gene products currently targeted by drug therapies, eight of them are modulated by Protandim in the same direction that is proposed to be beneficial and caused by the drug. PubMed:22020111

Appears in Networks:

path(MESH:"Alzheimer Disease") decreases p(HGNC:TSHZ1) View Subject | View Object

In Alzheimer disease, 66 genes were identified that are also modulated by Protandim at the gene expression level. Of these 66 genes, the first 43 of them (65%) were regulated by Protandim in the opposing direction to that taken by the Alzheimer disease process. The beneficial effect of Protandim is further supported by the fact that of the 10 gene products currently targeted by drug therapies, eight of them are modulated by Protandim in the same direction that is proposed to be beneficial and caused by the drug. PubMed:22020111

Appears in Networks:

path(MESH:"Alzheimer Disease") decreases p(HGNC:TXN) View Subject | View Object

In Alzheimer disease, 66 genes were identified that are also modulated by Protandim at the gene expression level. Of these 66 genes, the first 43 of them (65%) were regulated by Protandim in the opposing direction to that taken by the Alzheimer disease process. The beneficial effect of Protandim is further supported by the fact that of the 10 gene products currently targeted by drug therapies, eight of them are modulated by Protandim in the same direction that is proposed to be beneficial and caused by the drug. PubMed:22020111

Appears in Networks:

path(MESH:"Alzheimer Disease") decreases p(HGNC:ACLY) View Subject | View Object

In Alzheimer disease, 66 genes were identified that are also modulated by Protandim at the gene expression level. Of these 66 genes, the first 43 of them (65%) were regulated by Protandim in the opposing direction to that taken by the Alzheimer disease process. The beneficial effect of Protandim is further supported by the fact that of the 10 gene products currently targeted by drug therapies, eight of them are modulated by Protandim in the same direction that is proposed to be beneficial and caused by the drug. PubMed:22020111

Appears in Networks:

path(MESH:"Alzheimer Disease") decreases p(HGNC:ATAD2) View Subject | View Object

In Alzheimer disease, 66 genes were identified that are also modulated by Protandim at the gene expression level. Of these 66 genes, the first 43 of them (65%) were regulated by Protandim in the opposing direction to that taken by the Alzheimer disease process. The beneficial effect of Protandim is further supported by the fact that of the 10 gene products currently targeted by drug therapies, eight of them are modulated by Protandim in the same direction that is proposed to be beneficial and caused by the drug. PubMed:22020111

Appears in Networks:

path(MESH:"Alzheimer Disease") decreases p(HGNC:BECN1) View Subject | View Object

In Alzheimer disease, 66 genes were identified that are also modulated by Protandim at the gene expression level. Of these 66 genes, the first 43 of them (65%) were regulated by Protandim in the opposing direction to that taken by the Alzheimer disease process. The beneficial effect of Protandim is further supported by the fact that of the 10 gene products currently targeted by drug therapies, eight of them are modulated by Protandim in the same direction that is proposed to be beneficial and caused by the drug. PubMed:22020111

Appears in Networks:

path(MESH:"Alzheimer Disease") decreases p(HGNC:DHCR24) View Subject | View Object

In Alzheimer disease, 66 genes were identified that are also modulated by Protandim at the gene expression level. Of these 66 genes, the first 43 of them (65%) were regulated by Protandim in the opposing direction to that taken by the Alzheimer disease process. The beneficial effect of Protandim is further supported by the fact that of the 10 gene products currently targeted by drug therapies, eight of them are modulated by Protandim in the same direction that is proposed to be beneficial and caused by the drug. PubMed:22020111

Appears in Networks:

path(MESH:"Alzheimer Disease") decreases p(HGNC:FGF2) View Subject | View Object

In Alzheimer disease, 66 genes were identified that are also modulated by Protandim at the gene expression level. Of these 66 genes, the first 43 of them (65%) were regulated by Protandim in the opposing direction to that taken by the Alzheimer disease process. The beneficial effect of Protandim is further supported by the fact that of the 10 gene products currently targeted by drug therapies, eight of them are modulated by Protandim in the same direction that is proposed to be beneficial and caused by the drug. PubMed:22020111

Appears in Networks:

path(MESH:"Alzheimer Disease") decreases p(HGNC:HTRA1) View Subject | View Object

In Alzheimer disease, 66 genes were identified that are also modulated by Protandim at the gene expression level. Of these 66 genes, the first 43 of them (65%) were regulated by Protandim in the opposing direction to that taken by the Alzheimer disease process. The beneficial effect of Protandim is further supported by the fact that of the 10 gene products currently targeted by drug therapies, eight of them are modulated by Protandim in the same direction that is proposed to be beneficial and caused by the drug. PubMed:22020111

Appears in Networks:

path(MESH:"Alzheimer Disease") decreases p(HGNC:PRKCE) View Subject | View Object

In Alzheimer disease, 66 genes were identified that are also modulated by Protandim at the gene expression level. Of these 66 genes, the first 43 of them (65%) were regulated by Protandim in the opposing direction to that taken by the Alzheimer disease process. The beneficial effect of Protandim is further supported by the fact that of the 10 gene products currently targeted by drug therapies, eight of them are modulated by Protandim in the same direction that is proposed to be beneficial and caused by the drug. PubMed:22020111

Appears in Networks:

path(MESH:"Alzheimer Disease") decreases p(HGNC:PRKDC) View Subject | View Object

In Alzheimer disease, 66 genes were identified that are also modulated by Protandim at the gene expression level. Of these 66 genes, the first 43 of them (65%) were regulated by Protandim in the opposing direction to that taken by the Alzheimer disease process. The beneficial effect of Protandim is further supported by the fact that of the 10 gene products currently targeted by drug therapies, eight of them are modulated by Protandim in the same direction that is proposed to be beneficial and caused by the drug. PubMed:22020111

Appears in Networks:

path(MESH:"Alzheimer Disease") decreases p(HGNC:SCD) View Subject | View Object

In Alzheimer disease, 66 genes were identified that are also modulated by Protandim at the gene expression level. Of these 66 genes, the first 43 of them (65%) were regulated by Protandim in the opposing direction to that taken by the Alzheimer disease process. The beneficial effect of Protandim is further supported by the fact that of the 10 gene products currently targeted by drug therapies, eight of them are modulated by Protandim in the same direction that is proposed to be beneficial and caused by the drug. PubMed:22020111

Appears in Networks:

path(MESH:"Alzheimer Disease") decreases p(HGNC:TUBB) View Subject | View Object

In Alzheimer disease, 66 genes were identified that are also modulated by Protandim at the gene expression level. Of these 66 genes, the first 43 of them (65%) were regulated by Protandim in the opposing direction to that taken by the Alzheimer disease process. The beneficial effect of Protandim is further supported by the fact that of the 10 gene products currently targeted by drug therapies, eight of them are modulated by Protandim in the same direction that is proposed to be beneficial and caused by the drug. PubMed:22020111

Appears in Networks:

path(MESH:"Alzheimer Disease") decreases p(HGNC:UNG) View Subject | View Object

In Alzheimer disease, 66 genes were identified that are also modulated by Protandim at the gene expression level. Of these 66 genes, the first 43 of them (65%) were regulated by Protandim in the opposing direction to that taken by the Alzheimer disease process. The beneficial effect of Protandim is further supported by the fact that of the 10 gene products currently targeted by drug therapies, eight of them are modulated by Protandim in the same direction that is proposed to be beneficial and caused by the drug. PubMed:22020111

Appears in Networks:

path(MESH:"Alzheimer Disease") increases p(HGNC:ATP1A1) View Subject | View Object

In Alzheimer disease, 66 genes were identified that are also modulated by Protandim at the gene expression level. Of these 66 genes, the first 43 of them (65%) were regulated by Protandim in the opposing direction to that taken by the Alzheimer disease process. The beneficial effect of Protandim is further supported by the fact that of the 10 gene products currently targeted by drug therapies, eight of them are modulated by Protandim in the same direction that is proposed to be beneficial and caused by the drug. PubMed:22020111

Appears in Networks:

path(MESH:"Alzheimer Disease") increases p(HGNC:CTSD) View Subject | View Object

In Alzheimer disease, 66 genes were identified that are also modulated by Protandim at the gene expression level. Of these 66 genes, the first 43 of them (65%) were regulated by Protandim in the opposing direction to that taken by the Alzheimer disease process. The beneficial effect of Protandim is further supported by the fact that of the 10 gene products currently targeted by drug therapies, eight of them are modulated by Protandim in the same direction that is proposed to be beneficial and caused by the drug. PubMed:22020111

Appears in Networks:

path(MESH:"Alzheimer Disease") increases p(HGNC:GLRX) View Subject | View Object

In Alzheimer disease, 66 genes were identified that are also modulated by Protandim at the gene expression level. Of these 66 genes, the first 43 of them (65%) were regulated by Protandim in the opposing direction to that taken by the Alzheimer disease process. The beneficial effect of Protandim is further supported by the fact that of the 10 gene products currently targeted by drug therapies, eight of them are modulated by Protandim in the same direction that is proposed to be beneficial and caused by the drug. PubMed:22020111

Appears in Networks:

path(MESH:"Alzheimer Disease") positiveCorrelation p(HGNC:GLRX) View Subject | View Object

A likely explanation for the increased expression of GLRX2 (glutaredoxin 2) and NQO1 (NAD(P)H dehydrogenase, quinone 1) in colon carcinoma and of GLRX (glutaredoxin), HMOX1 (heme oxygenase-1), NQO1, and SOD1 (superoxide dismutase 1) in Alzheimer is that it represents an adaptive attempt to partially compensate for the increased level of oxidative stress associated with these diseases. These antioxidant genes are also upregulated by Protandim, which would provide additional antioxidant protection beyond that achieved by the ROS-dependent induction of these enzymes in the diseased tissues. PubMed:22020111

Appears in Networks:

path(MESH:"Alzheimer Disease") increases p(HGNC:HMOX1) View Subject | View Object

In Alzheimer disease, 66 genes were identified that are also modulated by Protandim at the gene expression level. Of these 66 genes, the first 43 of them (65%) were regulated by Protandim in the opposing direction to that taken by the Alzheimer disease process. The beneficial effect of Protandim is further supported by the fact that of the 10 gene products currently targeted by drug therapies, eight of them are modulated by Protandim in the same direction that is proposed to be beneficial and caused by the drug. PubMed:22020111

Appears in Networks:

path(MESH:"Alzheimer Disease") positiveCorrelation p(HGNC:HMOX1) View Subject | View Object

A likely explanation for the increased expression of GLRX2 (glutaredoxin 2) and NQO1 (NAD(P)H dehydrogenase, quinone 1) in colon carcinoma and of GLRX (glutaredoxin), HMOX1 (heme oxygenase-1), NQO1, and SOD1 (superoxide dismutase 1) in Alzheimer is that it represents an adaptive attempt to partially compensate for the increased level of oxidative stress associated with these diseases. These antioxidant genes are also upregulated by Protandim, which would provide additional antioxidant protection beyond that achieved by the ROS-dependent induction of these enzymes in the diseased tissues. PubMed:22020111

Appears in Networks:

path(MESH:"Alzheimer Disease") increases p(HGNC:IL6R) View Subject | View Object

In Alzheimer disease, 66 genes were identified that are also modulated by Protandim at the gene expression level. Of these 66 genes, the first 43 of them (65%) were regulated by Protandim in the opposing direction to that taken by the Alzheimer disease process. The beneficial effect of Protandim is further supported by the fact that of the 10 gene products currently targeted by drug therapies, eight of them are modulated by Protandim in the same direction that is proposed to be beneficial and caused by the drug. PubMed:22020111

Appears in Networks:

path(MESH:"Alzheimer Disease") increases p(HGNC:NPTX1) View Subject | View Object

In Alzheimer disease, 66 genes were identified that are also modulated by Protandim at the gene expression level. Of these 66 genes, the first 43 of them (65%) were regulated by Protandim in the opposing direction to that taken by the Alzheimer disease process. The beneficial effect of Protandim is further supported by the fact that of the 10 gene products currently targeted by drug therapies, eight of them are modulated by Protandim in the same direction that is proposed to be beneficial and caused by the drug. PubMed:22020111

Appears in Networks:

path(MESH:"Alzheimer Disease") increases p(HGNC:NQO1) View Subject | View Object

In Alzheimer disease, 66 genes were identified that are also modulated by Protandim at the gene expression level. Of these 66 genes, the first 43 of them (65%) were regulated by Protandim in the opposing direction to that taken by the Alzheimer disease process. The beneficial effect of Protandim is further supported by the fact that of the 10 gene products currently targeted by drug therapies, eight of them are modulated by Protandim in the same direction that is proposed to be beneficial and caused by the drug. PubMed:22020111

Appears in Networks:

path(MESH:"Alzheimer Disease") positiveCorrelation p(HGNC:NQO1) View Subject | View Object

A likely explanation for the increased expression of GLRX2 (glutaredoxin 2) and NQO1 (NAD(P)H dehydrogenase, quinone 1) in colon carcinoma and of GLRX (glutaredoxin), HMOX1 (heme oxygenase-1), NQO1, and SOD1 (superoxide dismutase 1) in Alzheimer is that it represents an adaptive attempt to partially compensate for the increased level of oxidative stress associated with these diseases. These antioxidant genes are also upregulated by Protandim, which would provide additional antioxidant protection beyond that achieved by the ROS-dependent induction of these enzymes in the diseased tissues. PubMed:22020111

Appears in Networks:

path(MESH:"Alzheimer Disease") increases p(HGNC:PHF1) View Subject | View Object

In Alzheimer disease, 66 genes were identified that are also modulated by Protandim at the gene expression level. Of these 66 genes, the first 43 of them (65%) were regulated by Protandim in the opposing direction to that taken by the Alzheimer disease process. The beneficial effect of Protandim is further supported by the fact that of the 10 gene products currently targeted by drug therapies, eight of them are modulated by Protandim in the same direction that is proposed to be beneficial and caused by the drug. PubMed:22020111

Appears in Networks:

path(MESH:"Alzheimer Disease") increases p(HGNC:PRKCD) View Subject | View Object

In Alzheimer disease, 66 genes were identified that are also modulated by Protandim at the gene expression level. Of these 66 genes, the first 43 of them (65%) were regulated by Protandim in the opposing direction to that taken by the Alzheimer disease process. The beneficial effect of Protandim is further supported by the fact that of the 10 gene products currently targeted by drug therapies, eight of them are modulated by Protandim in the same direction that is proposed to be beneficial and caused by the drug. PubMed:22020111

Appears in Networks:

path(MESH:"Alzheimer Disease") increases p(HGNC:PTGS2) View Subject | View Object

In Alzheimer disease, 66 genes were identified that are also modulated by Protandim at the gene expression level. Of these 66 genes, the first 43 of them (65%) were regulated by Protandim in the opposing direction to that taken by the Alzheimer disease process. The beneficial effect of Protandim is further supported by the fact that of the 10 gene products currently targeted by drug therapies, eight of them are modulated by Protandim in the same direction that is proposed to be beneficial and caused by the drug. PubMed:22020111

Appears in Networks:

path(MESH:"Alzheimer Disease") increases p(HGNC:RANBP9) View Subject | View Object

In Alzheimer disease, 66 genes were identified that are also modulated by Protandim at the gene expression level. Of these 66 genes, the first 43 of them (65%) were regulated by Protandim in the opposing direction to that taken by the Alzheimer disease process. The beneficial effect of Protandim is further supported by the fact that of the 10 gene products currently targeted by drug therapies, eight of them are modulated by Protandim in the same direction that is proposed to be beneficial and caused by the drug. PubMed:22020111

Appears in Networks:

path(MESH:"Alzheimer Disease") increases p(HGNC:SOD1) View Subject | View Object

In Alzheimer disease, 66 genes were identified that are also modulated by Protandim at the gene expression level. Of these 66 genes, the first 43 of them (65%) were regulated by Protandim in the opposing direction to that taken by the Alzheimer disease process. The beneficial effect of Protandim is further supported by the fact that of the 10 gene products currently targeted by drug therapies, eight of them are modulated by Protandim in the same direction that is proposed to be beneficial and caused by the drug. PubMed:22020111

Appears in Networks:

path(MESH:"Alzheimer Disease") positiveCorrelation p(HGNC:SOD1) View Subject | View Object

A likely explanation for the increased expression of GLRX2 (glutaredoxin 2) and NQO1 (NAD(P)H dehydrogenase, quinone 1) in colon carcinoma and of GLRX (glutaredoxin), HMOX1 (heme oxygenase-1), NQO1, and SOD1 (superoxide dismutase 1) in Alzheimer is that it represents an adaptive attempt to partially compensate for the increased level of oxidative stress associated with these diseases. These antioxidant genes are also upregulated by Protandim, which would provide additional antioxidant protection beyond that achieved by the ROS-dependent induction of these enzymes in the diseased tissues. PubMed:22020111

Appears in Networks:

path(MESH:"Alzheimer Disease") positiveCorrelation bp(MESH:"Oxidative Stress") View Subject | View Object

A likely explanation for the increased expression of GLRX2 (glutaredoxin 2) and NQO1 (NAD(P)H dehydrogenase, quinone 1) in colon carcinoma and of GLRX (glutaredoxin), HMOX1 (heme oxygenase-1), NQO1, and SOD1 (superoxide dismutase 1) in Alzheimer is that it represents an adaptive attempt to partially compensate for the increased level of oxidative stress associated with these diseases. These antioxidant genes are also upregulated by Protandim, which would provide additional antioxidant protection beyond that achieved by the ROS-dependent induction of these enzymes in the diseased tissues. PubMed:22020111

Appears in Networks:

path(MESH:"Alzheimer Disease") increases p(HGNC:SET) View Subject | View Object

In Alzheimer's disease, inhibition of PP2A activity by SET leads to hyper phosphorylation of the Tau protein [47]. PubMed:23454242

Appears in Networks:

path(MESH:"Alzheimer Disease") decreases act(p(FPLX:PPP2)) View Subject | View Object

In Alzheimer's disease, inhibition of PP2A activity by SET leads to hyper phosphorylation of the Tau protein [47]. PubMed:23454242

Appears in Networks:

path(MESH:"Alzheimer Disease") negativeCorrelation g(HGNC:PPP2CA) View Subject | View Object

Deficits in PP2A activity are in line with the reported down-regulation of PP2A catalytic C subunit at the gene (Loring et al.,2001), mRNA (Vogelsberg-Ragaglia et al.,2001) and protein (Sontag et al.,2004b) expression levels in AD. PubMed:24653673

Appears in Networks:

path(MESH:"Alzheimer Disease") association p(HGNC:GSK3B) View Subject | View Object

PP2A enzymes can also associate with protein kinases that have been linked to AD, such as glycogen synthase kinase 3β (GSK3β) and cyclin-dependent kinase 5 (cdk5; Plattner et al.,2006), and neuronal receptors, e.g., the NMDA receptor (Chan and Sucher, 2001) and the metabotropic glutamate receptor 5 (Mao et al., 2005; Arif et al., 2014). PubMed:24653673

Appears in Networks:

path(MESH:"Alzheimer Disease") association p(HGNC:CDK5) View Subject | View Object

PP2A enzymes can also associate with protein kinases that have been linked to AD, such as glycogen synthase kinase 3β (GSK3β) and cyclin-dependent kinase 5 (cdk5; Plattner et al.,2006), and neuronal receptors, e.g., the NMDA receptor (Chan and Sucher, 2001) and the metabotropic glutamate receptor 5 (Mao et al., 2005; Arif et al., 2014). PubMed:24653673

Appears in Networks:

path(MESH:"Alzheimer Disease") association a(MESH:"Receptors, N-Methyl-D-Aspartate") View Subject | View Object

PP2A enzymes can also associate with protein kinases that have been linked to AD, such as glycogen synthase kinase 3β (GSK3β) and cyclin-dependent kinase 5 (cdk5; Plattner et al.,2006), and neuronal receptors, e.g., the NMDA receptor (Chan and Sucher, 2001) and the metabotropic glutamate receptor 5 (Mao et al., 2005; Arif et al., 2014). PubMed:24653673

Appears in Networks:

path(MESH:"Alzheimer Disease") association p(HGNC:GRM5) View Subject | View Object

PP2A enzymes can also associate with protein kinases that have been linked to AD, such as glycogen synthase kinase 3β (GSK3β) and cyclin-dependent kinase 5 (cdk5; Plattner et al.,2006), and neuronal receptors, e.g., the NMDA receptor (Chan and Sucher, 2001) and the metabotropic glutamate receptor 5 (Mao et al., 2005; Arif et al., 2014). PubMed:24653673

Appears in Networks:

path(MESH:"Alzheimer Disease") negativeCorrelation act(complex(GO:"protein phosphatase type 2A complex")) View Subject | View Object

There is a significant decrease in total PP2A activity measured in AD cortical and hippocampal brain homogenates (Gong et al.,1993; Gong et al.,1995; Sontag et al.,2004b). PubMed:24653673

Appears in Networks:
Annotations
MeSH
Cerebral Cortex
MeSH
Hippocampus

path(MESH:"Alzheimer Disease") positiveCorrelation complex(GO:"protein phosphatase type 2A complex") View Subject | View Object

In contrast, “PP2A” expression levels are increased in AD astrocytes (Pei et al., 1997). PubMed:24653673

Appears in Networks:
Annotations
MeSH
Astrocytes

path(MESH:"Alzheimer Disease") negativeCorrelation act(complex(GO:"protein phosphatase type 2A complex")) View Subject | View Object

Collectively, those studies point to a central role for PP2A dysfunction in AD pathogenesis PubMed:24653673

Appears in Networks:

path(MESH:"Alzheimer Disease") negativeCorrelation r(HGNC:PPP2CA) View Subject | View Object

Deficits in PP2A activity are in line with the reported down-regulation of PP2A catalytic C subunit at the gene (Loring et al.,2001), mRNA (Vogelsberg-Ragaglia et al.,2001) and protein (Sontag et al.,2004b) expression levels in AD. PubMed:24653673

Appears in Networks:

path(MESH:"Alzheimer Disease") negativeCorrelation p(HGNC:PPP2CA) View Subject | View Object

Deficits in PP2A activity are in line with the reported down-regulation of PP2A catalytic C subunit at the gene (Loring et al.,2001), mRNA (Vogelsberg-Ragaglia et al.,2001) and protein (Sontag et al.,2004b) expression levels in AD. PubMed:24653673

Appears in Networks:

path(MESH:"Alzheimer Disease") negativeCorrelation g(HGNC:PPP2CB) View Subject | View Object

Deficits in PP2A activity are in line with the reported down-regulation of PP2A catalytic C subunit at the gene (Loring et al.,2001), mRNA (Vogelsberg-Ragaglia et al.,2001) and protein (Sontag et al.,2004b) expression levels in AD. PubMed:24653673

Appears in Networks:

path(MESH:"Alzheimer Disease") negativeCorrelation r(HGNC:PPP2CB) View Subject | View Object

Deficits in PP2A activity are in line with the reported down-regulation of PP2A catalytic C subunit at the gene (Loring et al.,2001), mRNA (Vogelsberg-Ragaglia et al.,2001) and protein (Sontag et al.,2004b) expression levels in AD. PubMed:24653673

Appears in Networks:

path(MESH:"Alzheimer Disease") negativeCorrelation p(HGNC:PPP2CB) View Subject | View Object

Deficits in PP2A activity are in line with the reported down-regulation of PP2A catalytic C subunit at the gene (Loring et al.,2001), mRNA (Vogelsberg-Ragaglia et al.,2001) and protein (Sontag et al.,2004b) expression levels in AD. PubMed:24653673

Appears in Networks:

path(MESH:"Alzheimer Disease") negativeCorrelation r(HGNC:PPP2R2C) View Subject | View Object

More specifically, decreased expression levels of PP2A regulatory Bγ (or PPP2R2C) and B’ε (or PPP2R5E) subunit mRNAs in the hippocampus (Vogelsberg-Ragaglia et al.,2001), and cortical Bα subunit (Sontag et al.,2004b) have been reported in AD. PubMed:24653673

Appears in Networks:
Annotations
MeSH
Hippocampus

path(MESH:"Alzheimer Disease") negativeCorrelation r(HGNC:PPP2R5E) View Subject | View Object

More specifically, decreased expression levels of PP2A regulatory Bγ (or PPP2R2C) and B’ε (or PPP2R5E) subunit mRNAs in the hippocampus (Vogelsberg-Ragaglia et al.,2001), and cortical Bα subunit (Sontag et al.,2004b) have been reported in AD. PubMed:24653673

Appears in Networks:
Annotations
MeSH
Hippocampus

path(MESH:"Alzheimer Disease") negativeCorrelation p(INTERPRO:"Protein phosphatase 2A regulatory subunit PR55") View Subject | View Object

More specifically, decreased expression levels of PP2A regulatory Bγ (or PPP2R2C) and B’ε (or PPP2R5E) subunit mRNAs in the hippocampus (Vogelsberg-Ragaglia et al.,2001), and cortical Bα subunit (Sontag et al.,2004b) have been reported in AD. PubMed:24653673

Appears in Networks:
Annotations
MeSH
Cerebral Cortex

path(MESH:"Alzheimer Disease") negativeCorrelation p(FPLX:PPP2, pmod(Me)) View Subject | View Object

Significantly, down-regulation of LCMT1 protein expression parallels the deficits in PP2A methylation observed in AD (Sontag et al.,2004a). PubMed:24653673

Appears in Networks:
Annotations
MeSH
Alzheimer Disease

path(MESH:"Alzheimer Disease") negativeCorrelation p(FPLX:PPP2, pmod(Me)) View Subject | View Object

Conversely, decreased PP2A methylation and PP2A/Bα levels in AD will disrupt normal PP2A-tau interactions (Sontag et al., 2007), thereby preventing PP2A-mediated tau dephosphorylation while allowing for enhanced binding of Fyn kinase or other regulators to the tau proteins. PubMed:24653673

Appears in Networks:

path(MESH:"Alzheimer Disease") negativeCorrelation p(FPLX:PPP2, pmod(Me)) View Subject | View Object

The deregulation of PP2A methylation in AD is especially interesting, not only because it can lead to a loss of PP2A/Bα, a major tau regulator, but also because PP2A methylation state is intimately linked to the integrity of one-carbon metabolism, which regulates SAM supply (Reviewed in Fowler,2005). PubMed:24653673

Appears in Networks:

path(MESH:"Alzheimer Disease") positiveCorrelation p(HGNC:ANP32A) View Subject | View Object

Up-regulation of I1 PP2A and I2 PP2A, and mislocalization and cleavage of I2 PP2A, could underlie the inactivation of PP2A in AD neocortical neurons (Tanimukai et al.,2005). PubMed:24653673

Appears in Networks:
Annotations
MeSH
Neocortex
MeSH
Alzheimer Disease

path(MESH:"Alzheimer Disease") positiveCorrelation p(HGNC:SET) View Subject | View Object

Up-regulation of I1 PP2A and I2 PP2A, and mislocalization and cleavage of I2 PP2A, could underlie the inactivation of PP2A in AD neocortical neurons (Tanimukai et al.,2005). PubMed:24653673

Appears in Networks:
Annotations
MeSH
Neocortex
MeSH
Alzheimer Disease

path(MESH:"Alzheimer Disease") positiveCorrelation p(HGNC:SET, frag("?")) View Subject | View Object

Up-regulation of I1 PP2A and I2 PP2A, and mislocalization and cleavage of I2 PP2A, could underlie the inactivation of PP2A in AD neocortical neurons (Tanimukai et al.,2005). PubMed:24653673

Appears in Networks:
Annotations
MeSH
Neocortex
MeSH
Alzheimer Disease

path(MESH:"Alzheimer Disease") negativeCorrelation p(HGNC:PTPA) View Subject | View Object

Decreased expression levels of PTPA in AD brain tissue may also lead to inactivation of PP2A by indirectly increasing levels of PP2A phosphorylated at the Tyr-307 site (Luo et al.,2013). PubMed:24653673

Appears in Networks:
Annotations
MeSH
Alzheimer Disease

path(MESH:"Alzheimer Disease") positiveCorrelation p(HGNC:MAPT, pmod(Ph, Thr, 231)) View Subject | View Object

This is potentially physiologically significant since phosphorylation of tau at Thr-231, a target site for ERK2, GSK3β, and cdk5, occurs early in AD and can further inhibit the ability of PP2A/Bα to dephosphorylate other major AD-tau phosphoepitopes (Landrieu et al.,2011). PubMed:24653673

Appears in Networks:

path(MESH:"Alzheimer Disease") negativeCorrelation complex(p(HGNC:PPP2CA), p(HGNC:PPP2R1A), p(INTERPRO:"Protein phosphatase 2A regulatory subunit PR55")) View Subject | View Object

Conversely, decreased PP2A methylation and PP2A/Bα levels in AD will disrupt normal PP2A-tau interactions (Sontag et al., 2007), thereby preventing PP2A-mediated tau dephosphorylation while allowing for enhanced binding of Fyn kinase or other regulators to the tau proteins. PubMed:24653673

Appears in Networks:

path(MESH:"Alzheimer Disease") negativeCorrelation complex(p(HGNC:PPP2CA), p(HGNC:PPP2R1A), p(INTERPRO:"Protein phosphatase 2A regulatory subunit PR55")) View Subject | View Object

The deregulation of PP2A methylation in AD is especially interesting, not only because it can lead to a loss of PP2A/Bα, a major tau regulator, but also because PP2A methylation state is intimately linked to the integrity of one-carbon metabolism, which regulates SAM supply (Reviewed in Fowler,2005). PubMed:24653673

Appears in Networks:

path(MESH:"Alzheimer Disease") negativeCorrelation complex(p(HGNC:PPP2CB), p(HGNC:PPP2R1A), p(INTERPRO:"Protein phosphatase 2A regulatory subunit PR55")) View Subject | View Object

Conversely, decreased PP2A methylation and PP2A/Bα levels in AD will disrupt normal PP2A-tau interactions (Sontag et al., 2007), thereby preventing PP2A-mediated tau dephosphorylation while allowing for enhanced binding of Fyn kinase or other regulators to the tau proteins. PubMed:24653673

Appears in Networks:

path(MESH:"Alzheimer Disease") negativeCorrelation complex(p(HGNC:PPP2CB), p(HGNC:PPP2R1A), p(INTERPRO:"Protein phosphatase 2A regulatory subunit PR55")) View Subject | View Object

The deregulation of PP2A methylation in AD is especially interesting, not only because it can lead to a loss of PP2A/Bα, a major tau regulator, but also because PP2A methylation state is intimately linked to the integrity of one-carbon metabolism, which regulates SAM supply (Reviewed in Fowler,2005). PubMed:24653673

Appears in Networks:

path(MESH:"Alzheimer Disease") negativeCorrelation complex(p(HGNC:MAPT), p(HGNC:PPP2CA), p(HGNC:PPP2R1A), p(INTERPRO:"Protein phosphatase 2A regulatory subunit PR55")) View Subject | View Object

Conversely, decreased PP2A methylation and PP2A/Bα levels in AD will disrupt normal PP2A-tau interactions (Sontag et al., 2007), thereby preventing PP2A-mediated tau dephosphorylation while allowing for enhanced binding of Fyn kinase or other regulators to the tau proteins. PubMed:24653673

Appears in Networks:

path(MESH:"Alzheimer Disease") negativeCorrelation complex(p(HGNC:MAPT), p(HGNC:PPP2CB), p(HGNC:PPP2R1A), p(INTERPRO:"Protein phosphatase 2A regulatory subunit PR55")) View Subject | View Object

Conversely, decreased PP2A methylation and PP2A/Bα levels in AD will disrupt normal PP2A-tau interactions (Sontag et al., 2007), thereby preventing PP2A-mediated tau dephosphorylation while allowing for enhanced binding of Fyn kinase or other regulators to the tau proteins. PubMed:24653673

Appears in Networks:

path(MESH:"Alzheimer Disease") positiveCorrelation p(HGNC:MAPT, pmod(Ph)) View Subject | View Object

Conversely, decreased PP2A methylation and PP2A/Bα levels in AD will disrupt normal PP2A-tau interactions (Sontag et al., 2007), thereby preventing PP2A-mediated tau dephosphorylation while allowing for enhanced binding of Fyn kinase or other regulators to the tau proteins. PubMed:24653673

Appears in Networks:

path(MESH:"Alzheimer Disease") positiveCorrelation complex(p(HGNC:FYN), p(HGNC:MAPT)) View Subject | View Object

Conversely, decreased PP2A methylation and PP2A/Bα levels in AD will disrupt normal PP2A-tau interactions (Sontag et al., 2007), thereby preventing PP2A-mediated tau dephosphorylation while allowing for enhanced binding of Fyn kinase or other regulators to the tau proteins. PubMed:24653673

Appears in Networks:

path(MESH:"Alzheimer Disease") association a(HBP:"straight filaments") View Subject | View Object

For the sake of completeness, we also refer to tau- 3R transgenic mice that developed another type of pathology in the hippocampus, e.g., straight fila- ments formed in aged mice older than 18 mo (Ishi- hara, 2001b), which was proposed to be relevant for AD, given the age-dependence. PubMed:12428809

Appears in Networks:

path(MESH:"Alzheimer Disease") positiveCorrelation p(HBP:"4R tau") View Subject | View Object

Evidently, this argues for critical levels of protein tau-4R in the pathology of FTD and by exten- sion, in AD. PubMed:12428809

Appears in Networks:

path(MESH:"Alzheimer Disease") negativeCorrelation bp(GO:"axonal transport") View Subject | View Object

The following proposition has been recently reit- erated that axonal transport in AD could become disrupted by increased neuronal concentrations of tau protein PubMed:12428809

Appears in Networks:

path(MESH:"Alzheimer Disease") association p(HGNC:MAPT, pmod(Ph, Ser, 396), pmod(Ph, Ser, 404)) View Subject | View Object

More- over, the unbound tau protein was hyperphospho- rylated and especially at the AD-2 epitope, e.g., an epitope shown to contain serine 396 and serine 404. PubMed:12428809

Appears in Networks:
Annotations
MeSH
Brain
MeSH
Spinal Cord

path(MESH:"Alzheimer Disease") positiveCorrelation p(HGNC:MAPT, pmod(Ph, Ser, 189)) View Subject | View Object

Similar findings have been observed in metabolically active rat brain slices, where a selective inhibition of PP2A with OA results in an aberrant phosphorylation of tau at the same residues seen in AD brains at serines (Ser) 198, 199, 202, 396, 404, 422 and 262 [11, 47, 48]. PubMed:22299660

Appears in Networks:

path(MESH:"Alzheimer Disease") positiveCorrelation p(HGNC:MAPT, pmod(Ph, Ser, 199)) View Subject | View Object

Similar findings have been observed in metabolically active rat brain slices, where a selective inhibition of PP2A with OA results in an aberrant phosphorylation of tau at the same residues seen in AD brains at serines (Ser) 198, 199, 202, 396, 404, 422 and 262 [11, 47, 48]. PubMed:22299660

Appears in Networks:

path(MESH:"Alzheimer Disease") positiveCorrelation p(HGNC:MAPT, pmod(Ph, Ser, 202)) View Subject | View Object

Similar findings have been observed in metabolically active rat brain slices, where a selective inhibition of PP2A with OA results in an aberrant phosphorylation of tau at the same residues seen in AD brains at serines (Ser) 198, 199, 202, 396, 404, 422 and 262 [11, 47, 48]. PubMed:22299660

Appears in Networks:

path(MESH:"Alzheimer Disease") positiveCorrelation p(HGNC:MAPT, pmod(Ph, Ser, 396)) View Subject | View Object

Similar findings have been observed in metabolically active rat brain slices, where a selective inhibition of PP2A with OA results in an aberrant phosphorylation of tau at the same residues seen in AD brains at serines (Ser) 198, 199, 202, 396, 404, 422 and 262 [11, 47, 48]. PubMed:22299660

Appears in Networks:

path(MESH:"Alzheimer Disease") positiveCorrelation p(HGNC:MAPT, pmod(Ph, Ser, 404)) View Subject | View Object

Similar findings have been observed in metabolically active rat brain slices, where a selective inhibition of PP2A with OA results in an aberrant phosphorylation of tau at the same residues seen in AD brains at serines (Ser) 198, 199, 202, 396, 404, 422 and 262 [11, 47, 48]. PubMed:22299660

Appears in Networks:

path(MESH:"Alzheimer Disease") positiveCorrelation p(HGNC:MAPT, pmod(Ph, Ser, 422)) View Subject | View Object

Similar findings have been observed in metabolically active rat brain slices, where a selective inhibition of PP2A with OA results in an aberrant phosphorylation of tau at the same residues seen in AD brains at serines (Ser) 198, 199, 202, 396, 404, 422 and 262 [11, 47, 48]. PubMed:22299660

Appears in Networks:

path(MESH:"Alzheimer Disease") positiveCorrelation p(HGNC:MAPT, pmod(Ph, Ser, 262)) View Subject | View Object

Similar findings have been observed in metabolically active rat brain slices, where a selective inhibition of PP2A with OA results in an aberrant phosphorylation of tau at the same residues seen in AD brains at serines (Ser) 198, 199, 202, 396, 404, 422 and 262 [11, 47, 48]. PubMed:22299660

Appears in Networks:

path(MESH:"Alzheimer Disease") negativeCorrelation act(p(FPLX:PPP2)) View Subject | View Object

Several observations showing reduced PP2A activity by 30% in the frontal cortex in AD [55], were followed by a number of studies of PP2A mRNA and proteins. PubMed:22299660

Appears in Networks:
Annotations
MeSH
Frontal Lobe

path(MESH:"Alzheimer Disease") negativeCorrelation act(p(FPLX:PPP2)) View Subject | View Object

To sum up, PP2A activity is decreased in brain of AD, as revealed by using different approaches in different laboratories. PubMed:22299660

Appears in Networks:
Annotations
MeSH
Brain

path(MESH:"Alzheimer Disease") negativeCorrelation r(HGNC:PPP2CA) View Subject | View Object

Decreased mRNA levels of PP2A C have been reported in the CA3 region of AD hippocampus by in situ RNA hybridisation [56]. Moreover, microarray RNA analysis carried out to compare the expression of more than 7,000 gene in the amygdala, cingulate cortex, striatum and cerebellum dis- closed down-regulation of the catalytic subunit PP2A C in AD [57]. This has been further corroborated by quantitative TaqMan PCR showing reduced PP2A C mRNA expression levels in the hippocampus, but not in the frontal cortex, in AD cases with disease progression Fig. (1). PubMed:22299660

Appears in Networks:
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MeSH
CA3 Region, Hippocampal

path(MESH:"Alzheimer Disease") negativeCorrelation r(HGNC:PPP2CB) View Subject | View Object

Decreased mRNA levels of PP2A C have been reported in the CA3 region of AD hippocampus by in situ RNA hybridisation [56]. Moreover, microarray RNA analysis carried out to compare the expression of more than 7,000 gene in the amygdala, cingulate cortex, striatum and cerebellum dis- closed down-regulation of the catalytic subunit PP2A C in AD [57]. This has been further corroborated by quantitative TaqMan PCR showing reduced PP2A C mRNA expression levels in the hippocampus, but not in the frontal cortex, in AD cases with disease progression Fig. (1). PubMed:22299660

Appears in Networks:
Annotations
MeSH
CA3 Region, Hippocampal

path(MESH:"Alzheimer Disease") negativeCorrelation p(FPLX:PPP2C) View Subject | View Object

Analyses of protein expression by using gel electrophore- sis and western blotting have shown not only a reduction of PP2A C expression levels but also a marked reduction of B55, thus indicating that PP2A impairment is the result of combined effects of different subunits [60]. PubMed:22299660

Appears in Networks:

path(MESH:"Alzheimer Disease") negativeCorrelation p(HGNC:PPP2R2A) View Subject | View Object

Analyses of protein expression by using gel electrophore- sis and western blotting have shown not only a reduction of PP2A C expression levels but also a marked reduction of B55, thus indicating that PP2A impairment is the result of combined effects of different subunits [60]. PubMed:22299660

Appears in Networks:

path(MESH:"Alzheimer Disease") negativeCorrelation p(FPLX:PPP2C, pmod(Me, Leu, 309)) View Subject | View Object

PP2A C methylation at Leu309 is reduced in AD and this seems to contribute to PP2A C dysfunction by impairing the assembly of the trimer [77, 78]. PubMed:22299660

Appears in Networks:

path(MESH:"Alzheimer Disease") negativeCorrelation p(HGNC:ICMT) View Subject | View Object

Complementing these findings, immu- nohistochemical and western blot studies have shown re- duced expression of PPMT [77], and up-regulation of the PP2A inhibitors I 1 and I 2 in AD cases [79, 80]. PubMed:22299660

Appears in Networks:

path(MESH:"Alzheimer Disease") positiveCorrelation p(HGNC:ANP32A) View Subject | View Object

Complementing these findings, immu- nohistochemical and western blot studies have shown re- duced expression of PPMT [77], and up-regulation of the PP2A inhibitors I 1 and I 2 in AD cases [79, 80]. PubMed:22299660

Appears in Networks:

path(MESH:"Alzheimer Disease") positiveCorrelation p(HGNC:SET) View Subject | View Object

Complementing these findings, immu- nohistochemical and western blot studies have shown re- duced expression of PPMT [77], and up-regulation of the PP2A inhibitors I 1 and I 2 in AD cases [79, 80]. PubMed:22299660

Appears in Networks:

path(MESH:"Alzheimer Disease") positiveCorrelation p(FPLX:PPP2C, pmod(Ph, Tyr, 307)) View Subject | View Object

High levels of PP2A C phosphorylated at Tyr307 have been reported in the entorhinal cortex, hippocampus and frontal cortex in AD compared to controls [81]. PubMed:22299660

Appears in Networks:
Annotations
MeSH
Entorhinal Cortex
MeSH
Frontal Lobe
MeSH
Hippocampus

path(MESH:"Alzheimer Disease") decreases p(HGNCGENEFAMILY:"DNAJ (HSP40) heat shock proteins") View Subject | View Object

Among repressed genes, HSP40s were found to show significant changes as a family, with 62% of overall 48 HSP40 family members repressed in aging brain (superior frontal gyrus), 51% repressed in AD, and 41% repressed in both aging and AD. PubMed:27491084

Appears in Networks:

path(MESH:"Alzheimer Disease") increases p(HGNC:HSPB1) View Subject | View Object

The importance of sHSPs in disease was originally noted from the observations that HSPB1 and CRYAB were overexpressed in AD brains (Shinohara et al., 1993; Renkawek et al., 1994a,b) and HSPB1, CRYAB, HSPB6 and HSPB8 were associated with AD plaques (Shao et al., 2012). PubMed:27491084

Appears in Networks:
Annotations
MeSH
Brain

path(MESH:"Alzheimer Disease") increases p(HGNC:CRYAB) View Subject | View Object

The importance of sHSPs in disease was originally noted from the observations that HSPB1 and CRYAB were overexpressed in AD brains (Shinohara et al., 1993; Renkawek et al., 1994a,b) and HSPB1, CRYAB, HSPB6 and HSPB8 were associated with AD plaques (Shao et al., 2012). PubMed:27491084

Appears in Networks:
Annotations
MeSH
Brain

path(MESH:"Alzheimer Disease") increases p(FPLX:HSPB) View Subject | View Object

Furthermore, sHSPs were found to be consistently upregulated in the aging human brain and in the context of neurodegenerative diseases (Brehme et al., 2014). PubMed:27491084

Appears in Networks:
Annotations
MeSH
Brain

path(MESH:"Alzheimer Disease") negativeCorrelation bp(GO:macroautophagy) View Subject | View Object

Since Nixon and colleagues first reported the pathological evidence of defective macroautophagy in EM images in the AD brain, similar observations have been made in cellular and animal models of AD [2,3,7,14] PubMed:29758300

Appears in Networks:

path(MESH:"Alzheimer Disease") negativeCorrelation bp(GO:macroautophagy) View Subject | View Object

Defects in macroautophagy in AD are supported by additional lines of evidence PubMed:29758300

Appears in Networks:

path(MESH:"Alzheimer Disease") negativeCorrelation bp(GO:macroautophagy) View Subject | View Object

Maintenance of neuronal macroautophagy can counteract AD pathology [22,23]. PubMed:29758300

Appears in Networks:
Annotations
MeSH
Neurons

path(MESH:"Alzheimer Disease") negativeCorrelation bp(GO:macroautophagy) View Subject | View Object

These results may be attributed to coincidental evidence of the involvement of Beclin 1 in VPS34-mediated trafficking pathways including macroautophagy and endocytosis [37], both of which are pronouncedly affected in AD pathology [38] PubMed:29758300

Appears in Networks:

path(MESH:"Alzheimer Disease") increases complex(a(GO:autophagosome), a(HBP:"dystrophic neurite")) View Subject | View Object

Robust AV accumulation in dystrophic neurites from biopsy tissues from patients with AD implicate a compromised state of autophagic flux PubMed:29758300

Appears in Networks:

path(MESH:"Alzheimer Disease") negativeCorrelation bp(GO:autophagy) View Subject | View Object

Robust AV accumulation in dystrophic neurites from biopsy tissues from patients with AD implicate a compromised state of autophagic flux PubMed:29758300

Appears in Networks:

path(MESH:"Alzheimer Disease") positiveCorrelation a(GO:autolysosome) View Subject | View Object

Other studies have also demonstrated the accumulation of autolysosomes in the AD brain and experimentally when lysosomal proteolysis is compromised via genetic knockdown of specific cathepsins or use of pharmacological inhibition of lysosomes [2,3,15] PubMed:29758300

Appears in Networks:
Annotations
MeSH
Brain

path(MESH:"Alzheimer Disease") negativeCorrelation bp(GO:"lysosomal protein catabolic process") View Subject | View Object

Such evidence of lysosomal proteolytic failure in AD brain further strengthens the concept that impaired macroautophagy in AD is a critical event PubMed:29758300

Appears in Networks:
Annotations
MeSH
Brain

path(MESH:"Alzheimer Disease") negativeCorrelation p(HGNC:BECN1) View Subject | View Object

For example, levels of Beclin 1, a key component of the class III type phosphoinositide 3-kinase/VPS34 complex essential to the pre-autophagosomal structure (PAS), has been suggested to be reduced in AD brains [16,17], with Rohn et al. demonstrating the cleavage of Beclin 1 by caspase-3 in the AD brain and colocalization of the cleaved product with NFTs [16]. PubMed:29758300

Appears in Networks:
Annotations
MeSH
Brain

path(MESH:"Alzheimer Disease") decreases p(HGNC:BECN1) View Subject | View Object

In line with this, reduced Beclin 1 levels, as seen in AD models [16], increase the levels of intracellular and extracellular Aβ peptides, supporting the role of macroautophagy in the generation and degradation of Aβ [33,35]. PubMed:29758300

Appears in Networks:

path(MESH:"Alzheimer Disease") association p(HGNC:PSEN1, var("?")) View Subject | View Object

Furthermore, presenilin-1, the most common mutation associated with early-onset familial AD (FAD), plays an essential role in calcium homeostasis and maintaining acidic lysosomal pH, with FAD-associated mutations disrupting calcium-dependent vATPase function in lysosomes [7,18–20] PubMed:29758300

Appears in Networks:

path(MESH:"Alzheimer Disease") increases a(GO:lysosome) View Subject | View Object

Recently, a comprehensive investigation utilizing gene expression analysis of the hippocampal region (CA1) of patients with Alzheimer’s disease identified that autophagosome formation and lysosomal biogenesis genes were upregulated at early stages of AD [21] PubMed:29758300

Appears in Networks:
Annotations
MeSH
CA1 Region, Hippocampal

path(MESH:"Alzheimer Disease") increases a(GO:autophagosome) View Subject | View Object

Recently, a comprehensive investigation utilizing gene expression analysis of the hippocampal region (CA1) of patients with Alzheimer’s disease identified that autophagosome formation and lysosomal biogenesis genes were upregulated at early stages of AD [21] PubMed:29758300

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MeSH
CA1 Region, Hippocampal

path(MESH:"Alzheimer Disease") positiveCorrelation p(HGNC:SNCA) View Subject | View Object

While misfolding of Aβ peptide and hyperphosphorylation of tau are recognized as pathogenic mechanisms of AD, accumulation of α-synuclein, which is recognized more as a risk factor for Parkinson’s disease (PD), also plays a pathological role in AD [29]. PubMed:29758300

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path(MESH:"Alzheimer Disease") negativeCorrelation bp(GO:endocytosis) View Subject | View Object

These results may be attributed to coincidental evidence of the involvement of Beclin 1 in VPS34-mediated trafficking pathways including macroautophagy and endocytosis [37], both of which are pronouncedly affected in AD pathology [38] PubMed:29758300

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path(MESH:"Alzheimer Disease") association p(HGNC:MAPT) View Subject | View Object

Dysregulation of tau proteins can produce a spectrum of neurodegenerative diseases or tauopathies characterized by dementia and tau deposition, including AD, frontotemporal dementia (FTD), Niemann- Pick disease, corticobasal degeneration (CBD), tangle-only dementia (TOD) and progressive supranuclear palsy (PSP). PubMed:29758300

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path(MESH:"Alzheimer Disease") association a(HBP:"alpha-synuclein aggregates") View Subject | View Object

While AD is generally considered a disorder with two proteinopathies, other protein aggregates are also seen in AD, like α-synuclein PubMed:29758300

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path(MESH:"Alzheimer Disease") positiveCorrelation a(HBP:"alpha-synuclein aggregates") View Subject | View Object

First identified as a nonamyloid component of Aβ plaques in the AD brain, α-synuclein aggregates are detected in the majority of the brains of patients with AD [56,57]. PubMed:29758300

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Brain

path(MESH:"Alzheimer Disease") positiveCorrelation a(CHEBI:ceramide) View Subject | View Object

Sphingolipids are also strongly implicated in AD pathology, with upregulated levels of ceramide, a key component in sphingolipid metabolism, detected in the early phase of AD [80]. PubMed:29758300

Appears in Networks:

path(MESH:"Alzheimer Disease") positiveCorrelation p(HGNC:MAPT, pmod(Ph, Ser, 262)) View Subject | View Object

A recent study has demonstrated that activation of AMPKα1 enhances tau phosphorylation, while inhibition reduces tau phosphorylation at Ser-262, an epitope that is increased in early stages of AD, which promotes the autophagic degradation of tau [87] PubMed:29758300

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path(MESH:"Alzheimer Disease") association p(HGNC:TFEB) View Subject | View Object

Another modulator of A-LS implicated in AD pathology is transcription factor EB (TFEB), a master regulator of lysosome biogenesis PubMed:29758300

Appears in Networks:

path(MESH:"Alzheimer Disease") association p(HGNC:PICALM, var("?")) View Subject | View Object

Multiple large-scale GWAS demonstrate that variants of PICALM (phosphatidylinositol-L-binding clathrin assembly protein involved in endocytosis) are significantly associated with AD [90,93,94]. PubMed:29758300

Appears in Networks:

path(MESH:"Alzheimer Disease") positiveCorrelation p(HGNC:BIN1) View Subject | View Object

Higher expression of BIN1 has been reported in AD brains, and suppression of BIN1 reduces tau toxicity, suggesting BIN1 involvement in tau pathology, as well [104]. PubMed:29758300

Appears in Networks:

path(MESH:"Alzheimer Disease") association p(HGNC:VPS35, var("?")) View Subject | View Object

VPS35 mutations have been shown to disrupt macroautophagy [113] and mitochondrial function [114] and are associated with AD and PD [102,115]. PubMed:29758300

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path(MESH:"Alzheimer Disease") association p(HGNC:SORL1) View Subject | View Object

One intriguing molecule that interacts with VPS35 is SORL1, a VPS10P-domain receptor protein that has been linked to autosomal dominant early-onset AD [116,117]. PubMed:29758300

Appears in Networks:

path(MESH:"Alzheimer Disease") increases bp(GO:mitophagy) View Subject | View Object

A recent study reported that mitophagy is robustly induced in AD brains and in vitro models of mutant APP, accompanied with abnormal accumulation of depoloarized mitochondria [126] PubMed:29758300

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MeSH
Brain

path(MESH:"Alzheimer Disease") positiveCorrelation p(HGNC:PRKN) View Subject | View Object

The E3 ligase Parkin, a protein implicated in Parkinson’s disease, creates an autophagy signal on mitochondria and also tags proteins elsewhere for proteasomal degradation (Yoshii et al. 2011). PubMed:22908190

Appears in Networks:

path(MESH:"Alzheimer Disease") positiveCorrelation p(HGNC:MAPT, pmod(Ub)) View Subject | View Object

In AD, tau is ubiquitinated, in Parkinson’s disease and dementia with Lewy bodies, it is a-synuclein, and in ALS and FTLD-U, it is TDP-43 PubMed:22908190

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path(MESH:"Alzheimer Disease") positiveCorrelation p(HBP:"UBB+1") View Subject | View Object

UBB+1 protein accumulates in brains affected by AD and other diseases such as Pick’s disease and Huntington’s disease (Fischer et al. 2003). PubMed:22908190

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Brain

path(MESH:"Alzheimer Disease") association p(HGNC:UCHL1) View Subject | View Object

Although UCH-L1 is genetically associated with Parkinson’s disease (i.e., it is the PARK5 gene; Belin and Westerlund 2008), it has also been implicated in the pathogenesis of AD PubMed:22908190

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path(MESH:"Alzheimer Disease") association p(HGNC:UBQLN1) View Subject | View Object

Next, ubiquilin-1 has been reported to be genetically linked to AD PubMed:22908190

Appears in Networks:

path(MESH:"Alzheimer Disease") positiveCorrelation p(HGNC:UBQLN1, var("?")) View Subject | View Object

An intronic polymorphism involving alternative splicing of exon 8 in the ubiquilin 1 gene (UBQLN1), which is genetically located near a well-established linkage peak for AD on chromosome 9q22, has been associated with increased risk for late-onset AD (Bertram et al. 2005). PubMed:22908190

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path(MESH:"Alzheimer Disease") negativeCorrelation act(a(GO:synapse)) View Subject | View Object

The earliest symptoms of AD are believed to be due to synaptic dysfunction, and in this context, numerous studies have established a significant role of the UPS in the regulation of synaptic plasticity. PubMed:22908190

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path(MESH:"Alzheimer Disease") negativeCorrelation act(a(GO:synapse)) View Subject | View Object

Synaptic loss has long been documented in AD brain (Gonatas et al. 1967) and, as expected, is strongly correlated with the degree of cognitive impairment (Terry et al. 1991). PubMed:22908190

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MeSH
Brain

path(MESH:"Alzheimer Disease") association bp(GO:autophagy) View Subject | View Object

Indeed, many recent studies suggest the involvement of autophagy in the pathogenesis of AD PubMed:22908190

Appears in Networks:

path(MESH:"Alzheimer Disease") association bp(GO:autophagy) View Subject | View Object

For example, immunocytochemistry showing the presence of K63- linked polyubiquitin in a fraction of the NFTs in AD cortex (Paine et al. 2009) suggests an active involvement of autophagy in the mechanism of AD. PubMed:22908190

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MeSH
Alzheimer Disease

path(MESH:"Alzheimer Disease") negativeCorrelation bp(GO:endocytosis) View Subject | View Object

A continuum of pathological changes of the lysosomal network unfolds in neurons as Alzheimer disease progresses, including dysregulation of endocytosis, increased lysosome biogenesis and, later, progressive failure of lysosomal clearance mechanisms (Fig. 6; Nixon et al. 2006). PubMed:22908190

Appears in Networks:

path(MESH:"Alzheimer Disease") negativeCorrelation bp(GO:endocytosis) View Subject | View Object

Pathological Rab5 activation driving endocytic dysfunction in AD may negatively impact longterm potentiation (LTP) and long-term depression (LTD) aspects of synaptic plasticity closely associated with learning and memory (Kessels et al. 2009) PubMed:22908190

Appears in Networks:

path(MESH:"Alzheimer Disease") positiveCorrelation a(GO:lysosome) View Subject | View Object

A continuum of pathological changes of the lysosomal network unfolds in neurons as Alzheimer disease progresses, including dysregulation of endocytosis, increased lysosome biogenesis and, later, progressive failure of lysosomal clearance mechanisms (Fig. 6; Nixon et al. 2006). PubMed:22908190

Appears in Networks:

path(MESH:"Alzheimer Disease") negativeCorrelation act(a(GO:lysosome)) View Subject | View Object

The profuse and selective accumulation of AVs in neurons in AD reflects a defect in the clearance of AVs by lysosomes rather than an abnormally elevated induction of autophagy PubMed:22908190

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MeSH
Neurons

path(MESH:"Alzheimer Disease") negativeCorrelation bp(GO:"lysosomal protein catabolic process") View Subject | View Object

A continuum of pathological changes of the lysosomal network unfolds in neurons as Alzheimer disease progresses, including dysregulation of endocytosis, increased lysosome biogenesis and, later, progressive failure of lysosomal clearance mechanisms (Fig. 6; Nixon et al. 2006). PubMed:22908190

Appears in Networks:

path(MESH:"Alzheimer Disease") positiveCorrelation p(HGNC:RAB7A) View Subject | View Object

Genes related to endocytosis, such as Rab5,Rab7, and Rab4, are among the earliest groups to showup-regulated transcription in AD(Ginsberg et al. 2010), and their corresponding proteins are abnormally recruited to endosomes, where they promote fusion and abnormal enlargement of early and late endosomes (Cataldo et al. 1997, 2008). PubMed:22908190

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path(MESH:"Alzheimer Disease") positiveCorrelation p(HGNC:RAB5A) View Subject | View Object

Genes related to endocytosis, such as Rab5,Rab7, and Rab4, are among the earliest groups to showup-regulated transcription in AD(Ginsberg et al. 2010), and their corresponding proteins are abnormally recruited to endosomes, where they promote fusion and abnormal enlargement of early and late endosomes (Cataldo et al. 1997, 2008). PubMed:22908190

Appears in Networks:

path(MESH:"Alzheimer Disease") positiveCorrelation p(HGNC:RAB4A) View Subject | View Object

Genes related to endocytosis, such as Rab5,Rab7, and Rab4, are among the earliest groups to showup-regulated transcription in AD(Ginsberg et al. 2010), and their corresponding proteins are abnormally recruited to endosomes, where they promote fusion and abnormal enlargement of early and late endosomes (Cataldo et al. 1997, 2008). PubMed:22908190

Appears in Networks:

path(MESH:"Alzheimer Disease") positiveCorrelation a(HBP:"dystrophic neurite") View Subject | View Object

AV accumulations are not specific to the degenerative phenomena of AD; however, in AD brain, the extensive numbers of dystrophic neurites (Masliah et al. 1993; Schmidt et al. 1994), their characteristic marked distension, and the fact that they are predominantly filled with AVs distinguish the pattern and magnitude of this pathology from that of other aging-related neurodegenerative diseases (Benzing et al. 1993). PubMed:22908190

Appears in Networks:

path(MESH:"Alzheimer Disease") positiveCorrelation a(GO:autophagosome) View Subject | View Object

The profuse and selective accumulation of AVs in neurons in AD reflects a defect in the clearance of AVs by lysosomes rather than an abnormally elevated induction of autophagy PubMed:22908190

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MeSH
Neurons

path(MESH:"Alzheimer Disease") positiveCorrelation p(HGNC:APP, var("?")) View Subject | View Object

App promoter polymorphisms that increase APP expression are also associated with early-onset AD (Athan et al. 2002). PubMed:22908190

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path(MESH:"Alzheimer Disease") positiveCorrelation p(HGNC:APP, var("?")) View Subject | View Object

These findings support a longstanding hypothesis that the App gene on the trisomic copy of human chromosome 21 (HSA21) in Down syndrome (DS) is principally responsible for the invariant early development of AD in DS individuals (Margallo-Lana et al. 2004). PubMed:22908190

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Down Syndrome

path(MESH:"Alzheimer Disease") association g(HBP:"APOE e4") View Subject | View Object

Acceleration of endosome pathology is also seen in individuals who inherit the 14 allele of APOE, a key mediator of neuronal cholesterol transport and the major genetic risk factor for late-onset AD (Cataldo et al. 2000). PubMed:22908190

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Neurons

path(MESH:"Alzheimer Disease") negativeCorrelation bp(GO:"axonal transport") View Subject | View Object

AVs and lysosomes constitute more than 95% of the organelles in dystrophic neuritic swellings in AD and AD mouse models, implying a cargo-specific defect in axonal transport, rather than a global one. PubMed:22908190

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MeSH
Alzheimer Disease

path(MESH:"Alzheimer Disease") positiveCorrelation a(GO:autophagosome) View Subject | View Object

This suggestion originates from the observed accumulation of autophagic vacuoles in neurons from affected brain regions in a number of neurodegenerative diseases, including Alzheimer’s disease, Parkinson’s disease, Creutzfeldt- Jakob disease, and many of the polyglutamine diseases [21–24]. PubMed:18930136

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MeSH
Neurons

path(MESH:"Alzheimer Disease") positiveCorrelation a(GO:autophagosome) View Subject | View Object

Alzheimer’s disease pathology features massive accumulation of autophagic vacuoles within large swellings along dystrophic and degenerating neurites in neocortical and hippocampal pyramidal neurons [21]. PubMed:18930136

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Hippocampus
MeSH
Neocortex
MeSH
Neurites
MeSH
Pyramidal Cells

path(MESH:"Alzheimer Disease") positiveCorrelation p(HGNC:MAPT, pmod(HBP:hyperphosphorylation)) View Subject | View Object

MAPT in AD and other tauopathies is hyperphosphorylated [29] and the hyperphosphorylation has been proposed to drive the missorting of MAPT. PubMed:30145931

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path(MESH:"Alzheimer Disease") positiveCorrelation a(HBP:"Tau oligomers") View Subject | View Object

Whereas control brain homogenate exhibited mainly Tau monomer, the AD brain contained a range of Tau assemblies ranging from n = 1 to n > 20 (Fig. 7, A and B). PubMed:25887395

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MeSH
Brain

path(MESH:"Alzheimer Disease") positiveCorrelation a(HBP:"Tau aggregates") View Subject | View Object

Tau from control brain purified in the monomer fraction (Figure 8A), while tau from AD brain distributed across multiple fractions, corresponding to monomer and larger assem- blies (Figure 8B). PubMed:29988016

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Brain

path(MESH:"Alzheimer Disease") positiveCorrelation p(HGNC:CHRNA7) View Subject | View Object

AD brains show an upregulation of CHRNA7 (acr-14 homolog in humans) (84), where it may mediate the Ab-induced tau pathology (85). PubMed:29191965

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Brain

path(MESH:"Alzheimer Disease") positiveCorrelation p(HGNC:MAPT, pmod(Ph)) View Subject | View Object

Phosphorylation is generally increased in AD and can be recognized by diagnostic antibodies against phosphoepitopes PubMed:29191965

Appears in Networks:

path(MESH:"Alzheimer Disease") positiveCorrelation p(HGNC:MAPT, pmod(Ph)) View Subject | View Object

For example, AD brain tau is;4-fold more phosphorylated than normal adult brain tau(93), but a high state of phosphorylation can also occur physiologically (e.g., in fetal brain or in hibernating animals (94). PubMed:29191965

Appears in Networks:

path(MESH:"Alzheimer Disease") positiveCorrelation p(HGNC:MAPT, pmod(Ph, Ser, 422)) View Subject | View Object

For example, both soluble and insoluble tau from transgenic worms generated by Kraemer and colleagues (66) was phosphorylated at most of the sites examined; however, the insoluble tau did not show reactivity at the AT8 and pS422 epitopes, which are pronounced in human AD tau. PubMed:29191965

Appears in Networks:

path(MESH:"Alzheimer Disease") positiveCorrelation p(HGNC:MAPT, pmod(Ph, Ser, 202)) View Subject | View Object

For example, both soluble and insoluble tau from transgenic worms generated by Kraemer and colleagues (66) was phosphorylated at most of the sites examined; however, the insoluble tau did not show reactivity at the AT8 and pS422 epitopes, which are pronounced in human AD tau. PubMed:29191965

Appears in Networks:

path(MESH:"Alzheimer Disease") positiveCorrelation p(HGNC:MAPT, pmod(Ph, Thr, 205)) View Subject | View Object

For example, both soluble and insoluble tau from transgenic worms generated by Kraemer and colleagues (66) was phosphorylated at most of the sites examined; however, the insoluble tau did not show reactivity at the AT8 and pS422 epitopes, which are pronounced in human AD tau. PubMed:29191965

Appears in Networks:

path(MESH:"Alzheimer Disease") positiveCorrelation p(HGNC:MAPT, pmod(HBP:hyperphosphorylation)) View Subject | View Object

In the pathological case of Alzheimer’s disease (AD) tau becomes hyperphosphorylated, detaches from the microtubules, misfolds, and mislocalizes to the somatodendritic compartment where it aggregates into neurofibrillary tangles. PubMed:25374103

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MeSH
Alzheimer Disease

path(MESH:"Alzheimer Disease") increases bp(GO:"microglial cell activation") View Subject | View Object

To investigate whether pathological Syk activation oc- curs in the brain of AD mouse models, we analyzed the brains of 116-week-old wild-type, Tg APPsw and Tg PS1/APPsw mice using high-resolution confocal micros- copy and immunofluorescence. All transgenic mice (Fig. 1b-e) exhibit an increased Iba-1 and GFAP reactiv- ity compared to wild-type littermates (Fig. 1a). Moreo- ver,wild-type some of the activated amoeboid microglia that are observed in transgenic mice are also strongly positive for pSyk (Fig. 1b-d). PubMed:28877763

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MeSH
Brain
MeSH
Alzheimer Disease

path(MESH:"Alzheimer Disease") positiveCorrelation p(HBP:"4R tau") View Subject | View Object

Tauopathies can be classified into three groups on the basis of the tau isoforms found in the aggregates: 4R tauopathies (including PSP, CBD and AGD), 3R tauopathies (for example, PiD) and 3R+4R tauopathies (for example, AD) PubMed:26631930

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path(MESH:"Alzheimer Disease") positiveCorrelation p(HBP:"3R tau") View Subject | View Object

Tauopathies can be classified into three groups on the basis of the tau isoforms found in the aggregates: 4R tauopathies (including PSP, CBD and AGD), 3R tauopathies (for example, PiD) and 3R+4R tauopathies (for example, AD) PubMed:26631930

Appears in Networks:

path(MESH:"Alzheimer Disease") positiveCorrelation p(HGNC:MAPT, pmod(Ph)) View Subject | View Object

In AD, the phosphorylation of tau is increased further to approximately eight phosphates per molecule. PubMed:26631930

Appears in Networks:

path(MESH:"Alzheimer Disease") positiveCorrelation p(HGNC:MAPT, pmod(Ph)) View Subject | View Object

This view is supported by a recent study showing that tau in a normal mouse brain is phosphorylated at many sites that were previously found to be phosphorylated in tau from the brains of patients with AD. PubMed:26631930

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MeSH
Brain

path(MESH:"Alzheimer Disease") positiveCorrelation p(HGNC:MAPT, pmod(Ph, Tyr, 18)) View Subject | View Object

The phosphorylation of tau at Tyr394 and Tyr18 is present in PHFs in the brains of individuals with AD. PubMed:26631930

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path(MESH:"Alzheimer Disease") negativeCorrelation act(p(HGNC:PPP2CA)) View Subject | View Object

Among them, PP2A is the main phosphatase:it accounts for ~70% of the human brain tau phosphatase activity, and its activity is reduced in the AD brain (by ~20% and ~40% in the grey and white matter, respectively) PubMed:26631930

Appears in Networks:

path(MESH:"Alzheimer Disease") positiveCorrelation p(HGNC:MAPT, pmod(HBP:hyperphosphorylation)) View Subject | View Object

Third, the phosphorylation of tau is often considered to enhance tau aggregation, as hyperphosphorylation and aggregation are both increased in AD PubMed:26631930

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path(MESH:"Alzheimer Disease") positiveCorrelation a(HBP:"Tau aggregates") View Subject | View Object

Third, the phosphorylation of tau is often considered to enhance tau aggregation, as hyperphosphorylation and aggregation are both increased in AD PubMed:26631930

Appears in Networks:

path(MESH:"Alzheimer Disease") decreases p(HGNC:MAPT, pmod(Ac, Lys, 259)) View Subject | View Object

Acetylation at Lys259, Lys290, Lys321 or Lys353 within the KXGS motifs occurs in normal tau, and is reduced in brains of individuals with AD and of rTg4510 transgenic mice PubMed:26631930

Appears in Networks:

path(MESH:"Alzheimer Disease") decreases p(HGNC:MAPT, pmod(Ac, Lys, 290)) View Subject | View Object

Acetylation at Lys259, Lys290, Lys321 or Lys353 within the KXGS motifs occurs in normal tau, and is reduced in brains of individuals with AD and of rTg4510 transgenic mice PubMed:26631930

Appears in Networks:

path(MESH:"Alzheimer Disease") decreases p(HGNC:MAPT, pmod(Ac, Lys, 321)) View Subject | View Object

Acetylation at Lys259, Lys290, Lys321 or Lys353 within the KXGS motifs occurs in normal tau, and is reduced in brains of individuals with AD and of rTg4510 transgenic mice PubMed:26631930

Appears in Networks:

path(MESH:"Alzheimer Disease") decreases p(HGNC:MAPT, pmod(Ac, Lys, 353)) View Subject | View Object

Acetylation at Lys259, Lys290, Lys321 or Lys353 within the KXGS motifs occurs in normal tau, and is reduced in brains of individuals with AD and of rTg4510 transgenic mice PubMed:26631930

Appears in Networks:

path(MESH:"Alzheimer Disease") positiveCorrelation p(HGNC:MAPT, pmod(Ac, Lys, 280)) View Subject | View Object

By contrast, acetylation of tau at Lys280 has been detected in AD and other tauopathies, including AGD, tangle-predominant senile dementia (TPSD), PiD, FTDP‑17 and PSP, and is pathological PubMed:26631930

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path(MESH:"Alzheimer Disease") positiveCorrelation p(HGNC:MAPT, pmod(Ac, Lys, 174)) View Subject | View Object

Recently, tau acetylation at Lys174 was identified in human AD brains as well. PubMed:26631930

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MeSH
Brain

path(MESH:"Alzheimer Disease") positiveCorrelation p(HGNC:MAPT, pmod(NGlyco)) View Subject | View Object

In human AD brains, but not in normal brains, tau is modified by N‑glycosylation, which is proposed to help to maintain and stabilize PHF structure PubMed:26631930

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MeSH
Brain

path(MESH:"Alzheimer Disease") positiveCorrelation p(HGNC:MAPT, pmod(HBP:nitration, Tyr, 18)) View Subject | View Object

The nitration of tau Tyr197 is found in the normal human brain and may have important physiological functions, whereas the nitration of Tyr18, Tyr29 and Tyr394 is detected only in AD or other tauopathies PubMed:26631930

Appears in Networks:

path(MESH:"Alzheimer Disease") positiveCorrelation p(HGNC:MAPT, pmod(HBP:nitration, Tyr, 29)) View Subject | View Object

The nitration of tau Tyr197 is found in the normal human brain and may have important physiological functions, whereas the nitration of Tyr18, Tyr29 and Tyr394 is detected only in AD or other tauopathies PubMed:26631930

Appears in Networks:

path(MESH:"Alzheimer Disease") positiveCorrelation p(HGNC:MAPT, pmod(HBP:nitration, Tyr, 394)) View Subject | View Object

The nitration of tau Tyr197 is found in the normal human brain and may have important physiological functions, whereas the nitration of Tyr18, Tyr29 and Tyr394 is detected only in AD or other tauopathies PubMed:26631930

Appears in Networks:

path(MESH:"Alzheimer Disease") negativeCorrelation p(HGNC:MAPT, pmod(Me)) View Subject | View Object

In human AD brains, PHF-tau is methylated at fewer sites than is tau from normal human brains PubMed:26631930

Appears in Networks:

path(MESH:"Alzheimer Disease") increases p(HGNC:MAPT, frag("?")) View Subject | View Object

The truncation of tau occurs in AD and in other tauopathies PubMed:26631930

Appears in Networks:

path(MESH:"Alzheimer Disease") positiveCorrelation p(HGNC:MAPT, frag("26_230")) View Subject | View Object

For instance, a 20–22-kDa N‑terminal tau fragment (amino acids 26–230) was detected in an AD mouse model expressing a transgenic nerve growth factor (NGF)-specific antibody (AD11) and in the cerebrospinal fluid (CSF) of individuals with AD is neurotoxic in primary neurons PubMed:26631930

Appears in Networks:

path(MESH:"Alzheimer Disease") increases tloc(p(HGNC:MAPT), fromLoc(GO:axon), toLoc(MESH:"Dendritic Spines")) View Subject | View Object

In human AD brains, the missorting of tau into dendrites represents one of the early signs of neurodegeneration PubMed:26631930

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MeSH
Alzheimer Disease

path(MESH:"Alzheimer Disease") positiveCorrelation p(HGNC:MAPT) View Subject | View Object

In AD and other tauopathies, the increase in dendritic tau levels is one of the first and most overt pathological abnormalities PubMed:26631930

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MeSH
Dendritic Spines

path(MESH:"Alzheimer Disease") increases a(CHEBI:"iron(0)") View Subject | View Object

Notably, this accumulation of iron was observed in the brain regions with reduced soluble tau levels, such as the cortex in AD, the substantia nigra in PD and various brain regions in several other tauopathies PubMed:26631930

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MeSH
Cerebral Cortex

path(MESH:"Alzheimer Disease") positiveCorrelation bp(GO:"neuron death") View Subject | View Object

In brains of individuals with AD, neuron loss in the superior temporal sulcus region exceeds the number of NFTs more than sevenfold, implying that the majority of neurons probably die without having developed NFTs PubMed:26631930

Appears in Networks:

path(MESH:"Alzheimer Disease") positiveCorrelation a(HBP:"Tau oligomers") View Subject | View Object

In an analogy to the evolution of concepts in the ‘amyloid cascade hypothesis’, which proposes that soluble oligomers — rather than insoluble aggregates of amyloid peptides — are the causative agents of neurodegeneration in AD, recent studies have suggested tau oligomers to be the toxic species, and indeed levels of SDS-stable tau oligomers are increased in AD and PSP brains. PubMed:26631930

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MeSH
Brain

path(MESH:"Alzheimer Disease") positiveCorrelation r(HGNC:BACE1, loc(GO:cytoplasm)) View Subject | View Object

For instance, measuring lncRNA BACE1 within the cytoplasm of the patients showed that its level in patients with Alzheimer’s was significantly higher than that in the control group PubMed:30663117

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MeSH
Alzheimer Disease

path(MESH:"Alzheimer Disease") positiveCorrelation r(HGNC:"BACE1-AS") View Subject | View Object

BACE1‐AS is transcribed by opposite strand BACE1. Its upregulation in patients with Alzheimer’s can be used as a new biomarker for the diagnosis of this disease. PubMed:30663117

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MeSH
Alzheimer Disease

path(MESH:"Alzheimer Disease") association g(HGNC:MIR384) View Subject | View Object

It was found that miR‐384, by binding to the 3′‐UTR sequence on BACE1 mRNA, could not only reduce expression in SH‐SY5Y cells but also attach to the 3′‐UTR sequence of the mRNA APP and reduce its expression, and this highlights the importance of miR‐384 in AD PubMed:30663117

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MeSH
Alzheimer Disease

path(MESH:"Alzheimer Disease") association g(HGNC:"MIR153-1") View Subject | View Object

Downregulation of miR‐153 increases the expression of APP and eventually, the production of β‐ameloid is promoted, increasing the risk of AD PubMed:30663117

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Alzheimer Disease

path(MESH:"Alzheimer Disease") association g(HGNC:"MIR101-1") View Subject | View Object

Besides, by directly affecting APP, miR‐101 can cause its downregulation, which ultimately provides the basis for AD PubMed:30663117

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Alzheimer Disease

path(MESH:"Alzheimer Disease") association g(HGNC:"MIR9-1") View Subject | View Object

As regards, the MAPKK2 pathway, miR‐9 has been shown to inhibit tangles neurofibrillary by inhibiting this pathway and to play an important role in preventing AD. PubMed:30663117

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MeSH
Alzheimer Disease

path(MESH:"Alzheimer Disease") decreases g(HGNC:"MIR9-1") View Subject | View Object

Comparing miR‐9 in patients with AD against healthy individuals shows a significant decrease of miR‐9 in patients with AD PubMed:30663117

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MeSH
Alzheimer Disease

path(MESH:"Alzheimer Disease") positiveCorrelation p(HGNC:RELA) View Subject | View Object

The results showed that the protein level of p65 sig- nificantly increased to 155.40¡13.39% in AD patient samples relative to control samples (p<0.05) (Fig. 1a). PubMed:21329555

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MeSH
Prefrontal Cortex

path(MESH:"Alzheimer Disease") positiveCorrelation p(HGNC:BACE1) View Subject | View Object

BACE1 mRNA levels were also markedly increased in the cortex of AD patients (126.40¡9.01% relative to controls, p<0.05) (Fig. 1b). PubMed:21329555

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MeSH
Prefrontal Cortex

path(MESH:"Alzheimer Disease") positiveCorrelation path(MESH:Inflammation) View Subject | View Object

Inflammation is one of major pathological changes in AD brains and NF-kB signalling plays an important role in inflammation and oxidative stress (Tong et al. 2005). PubMed:21329555

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MeSH
Brain

path(MESH:"Alzheimer Disease") association p(HGNC:IL6) View Subject | View Object

IL6 is another NF-κB – induced [256-260] pro-inflammatory cytokine up-regulated and integrally involved in the etio-pathogenesis of Alzheimer’s disease PubMed:28745240

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Alzheimer Disease

path(MESH:"Alzheimer Disease") positiveCorrelation p(HGNC:TNF) View Subject | View Object

Another known target of NF-κB, TNFα [266, 267] is also up-regulated in the cortex [268], cerebrospinal fluid, and the serum of Alzheimer’s disease patients PubMed:28745240

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Alzheimer Disease

path(MESH:"Alzheimer Disease") positiveCorrelation p(FPLX:NFkappaB) View Subject | View Object

Furthermore, A induced NF-B activity in glial and neuronal cells. NF-B is involved in inflammatory responses and is expressed in brains of AD patients [32]. PubMed:29179999

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Brain

path(MESH:"Alzheimer Disease") negativeCorrelation bp(GO:"regulation of synaptic plasticity") View Subject | View Object

In the nervous system, NF-κB has been proposed to serve important function by acting as a transcription regulator: it has roles in inflammation, neuronal survival, differentiation, apoptosis, neurite outgrowth, and synaptic plasticity [5], which are impaired in the progression of various neurodegenerative diseases especially in AD. PubMed:27288790

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Nervous System

path(MESH:"Alzheimer Disease") positiveCorrelation act(p(FPLX:NFkappaB)) View Subject | View Object

NF-κB activation has also been detected in the brains of AD pa- tients. PubMed:27288790

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Brain

path(MESH:"Alzheimer Disease") positiveCorrelation a(CHEBI:"reactive oxygen species") View Subject | View Object

Higher levels of ROS biomarkers are characteristic of AD patients in clinical and preclinical studies, resulting in the alteration of membrane proper- ties, such as fluidity, ion transport, enzyme activities, protein cross- linking, tau protein hyperphosphorylation, autophagic dysfunction and eventually neuron cell death [20]. PubMed:27288790

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path(MESH:"Alzheimer Disease") positiveCorrelation p(HGNC:TNF) View Subject | View Object

TNF-α [27], IL-1β [28], IL-18 [29], CXCL10 [30] and TGF-β1 [31] are known to be elevated in the AD brain. PubMed:27288790

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Brain

path(MESH:"Alzheimer Disease") positiveCorrelation p(HGNC:IL1B) View Subject | View Object

TNF-α [27], IL-1β [28], IL-18 [29], CXCL10 [30] and TGF-β1 [31] are known to be elevated in the AD brain. PubMed:27288790

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Brain

path(MESH:"Alzheimer Disease") positiveCorrelation p(HGNC:IL18) View Subject | View Object

TNF-α [27], IL-1β [28], IL-18 [29], CXCL10 [30] and TGF-β1 [31] are known to be elevated in the AD brain. PubMed:27288790

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Brain

path(MESH:"Alzheimer Disease") positiveCorrelation p(HGNC:CXCL10) View Subject | View Object

TNF-α [27], IL-1β [28], IL-18 [29], CXCL10 [30] and TGF-β1 [31] are known to be elevated in the AD brain. PubMed:27288790

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Brain

path(MESH:"Alzheimer Disease") positiveCorrelation p(HGNC:TGFB1) View Subject | View Object

TNF-α [27], IL-1β [28], IL-18 [29], CXCL10 [30] and TGF-β1 [31] are known to be elevated in the AD brain. PubMed:27288790

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Brain

path(MESH:"Alzheimer Disease") positiveCorrelation bp(GO:"MAPK cascade") View Subject | View Object

Reports have indicated that MAPK signaling pathways are excessively activated in AD. PubMed:27288790

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path(MESH:"Alzheimer Disease") positiveCorrelation a(CHEBI:pentosidine) View Subject | View Object

Two AGEs, such as pentosidine and glyceraldehyde derived pyridinium (GLAP), both found increased in AD brains, were able to upregulate BACE1 through their binding with RAGE and consequent activation of NF-κB, providing a pathologic link between diabetes and AD [49]. PubMed:27288790

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Brain

path(MESH:"Alzheimer Disease") positiveCorrelation a(HBP:GLAP) View Subject | View Object

Two AGEs, such as pentosidine and glyceraldehyde derived pyridinium (GLAP), both found increased in AD brains, were able to upregulate BACE1 through their binding with RAGE and consequent activation of NF-κB, providing a pathologic link between diabetes and AD [49]. PubMed:27288790

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Brain

path(MESH:"Alzheimer Disease") positiveCorrelation path(MESH:Inflammation) View Subject | View Object

Inflammation is a key pathological hall mark of AD [61,62], NF-κB is considered as a primary regulator of inflammatory processes [10]. PubMed:27288790

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path(MESH:"Alzheimer Disease") positiveCorrelation p(HGNC:PTGS2) View Subject | View Object

In addition, COX-2, mainly regulated by NF-κB, is notably upregulated in the brains of AD patients, which may be associated with the formation of Aβ plaque [65]. PubMed:27288790

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Brain

path(MESH:"Alzheimer Disease") positiveCorrelation m(MIRBASE:"hsa-mir-146a") View Subject | View Object

Elevated miRNA-146a in AD brain has been shown to also specifically target the interleukin-1 associated ki- nase-1 (IRAK-1) mRNAs, it is believed to contribute to altered innate immune responses and neuroinflammation in degenerating human brain cells and tissues in inflammatory neurodegenerative diseases including AD and in primary human brain cells stressed with ROS- generating metal sulfates [69]. PubMed:27288790

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Brain

path(MESH:"Alzheimer Disease") positiveCorrelation m(MIRBASE:"hsa-mir-155") View Subject | View Object

Specific up-regulation of miRNA-155 is observed in related immunopatho- logic conditions including MS and AD [70]. PubMed:27288790

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path(MESH:"Alzheimer Disease") positiveCorrelation complex(a(GO:"NF-kappaB complex"), p(HGNC:RELA)) View Subject | View Object

. Consistent with the cellular studies, increased immunostaining for NF-κB-p65 has been observed in neurons and their processes in the hippocampal formation and entorhinal cortex in AD PubMed:25652642

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Neurons
MeSH
Alzheimer Disease

path(MESH:"Alzheimer Disease") positiveCorrelation p(HGNC:RELA) View Subject | View Object

Comparison of the cellular distribution of NF-κB in the nucleus basalis of Meynert of AD and control patients showed that the proportion of large cholinergic neurons with elevated nuclear p65 was significantly increased in AD, suggesting an association between NF–κB functions and the process of cholinergic degeneration PubMed:25652642

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Alzheimer Disease

path(MESH:"Alzheimer Disease") positiveCorrelation act(complex(GO:"NF-kappaB complex")) View Subject | View Object

These observations substantiate a direct role of neuronal NF–κB activation in the pathogenesis of AD PubMed:25652642

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Neurons
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Alzheimer Disease

path(MESH:"Alzheimer Disease") positiveCorrelation complex(GO:"NF-kappaB complex") View Subject | View Object

Increased presence of activated glial cells presenting elevated NF-κB and HLA-DR expression are commonly observed around the Aβ plaques in postmortem AD tissue PubMed:25652642

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Alzheimer Disease

path(MESH:"Alzheimer Disease") positiveCorrelation complex(GO:"NF-kappaB complex") View Subject | View Object

Increased presence of NF-κB mediated IL-1β, IL-6, and TNF-α cytokines have been reported in the affected tissues, serum and CSF of AD patients PubMed:25652642

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Alzheimer Disease

path(MESH:"Alzheimer Disease") positiveCorrelation a(MESH:"HLA-DR Antigens") View Subject | View Object

Increased presence of activated glial cells presenting elevated NF-κB and HLA-DR expression are commonly observed around the Aβ plaques in postmortem AD tissue PubMed:25652642

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Alzheimer Disease

path(MESH:"Alzheimer Disease") positiveCorrelation p(HGNC:IL1B) View Subject | View Object

Increased presence of NF-κB mediated IL-1β, IL-6, and TNF-α cytokines have been reported in the affected tissues, serum and CSF of AD patients PubMed:25652642

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Alzheimer Disease

path(MESH:"Alzheimer Disease") positiveCorrelation p(HGNC:IL6) View Subject | View Object

Increased presence of NF-κB mediated IL-1β, IL-6, and TNF-α cytokines have been reported in the affected tissues, serum and CSF of AD patients PubMed:25652642

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Alzheimer Disease

path(MESH:"Alzheimer Disease") positiveCorrelation p(HGNC:TNF) View Subject | View Object

Increased presence of NF-κB mediated IL-1β, IL-6, and TNF-α cytokines have been reported in the affected tissues, serum and CSF of AD patients PubMed:25652642

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Alzheimer Disease

path(MESH:"Alzheimer Disease") positiveCorrelation m(HGNC:"MIR9-1") View Subject | View Object

Upregulation of several NF-κB regulated miRNAs such as miRNA-9, miRNA-34a, miRNA-125b, miRNA-146a, miRNA-155 and miRNA-339 5p have been observed in stressed primary human neuronalglial cells and in postmortem AD brain tissues PubMed:25652642

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Brain
MeSH
Neuroglia
MeSH
Alzheimer Disease

path(MESH:"Alzheimer Disease") positiveCorrelation m(HGNC:MIR34A) View Subject | View Object

Upregulation of several NF-κB regulated miRNAs such as miRNA-9, miRNA-34a, miRNA-125b, miRNA-146a, miRNA-155 and miRNA-339 5p have been observed in stressed primary human neuronalglial cells and in postmortem AD brain tissues PubMed:25652642

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Brain
MeSH
Neuroglia
MeSH
Alzheimer Disease

path(MESH:"Alzheimer Disease") positiveCorrelation m(HGNC:MIR125B1) View Subject | View Object

Upregulation of several NF-κB regulated miRNAs such as miRNA-9, miRNA-34a, miRNA-125b, miRNA-146a, miRNA-155 and miRNA-339 5p have been observed in stressed primary human neuronalglial cells and in postmortem AD brain tissues PubMed:25652642

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Brain
MeSH
Neuroglia
MeSH
Alzheimer Disease

path(MESH:"Alzheimer Disease") positiveCorrelation m(HGNC:MIR146A) View Subject | View Object

Upregulation of several NF-κB regulated miRNAs such as miRNA-9, miRNA-34a, miRNA-125b, miRNA-146a, miRNA-155 and miRNA-339 5p have been observed in stressed primary human neuronalglial cells and in postmortem AD brain tissues PubMed:25652642

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Brain
MeSH
Neuroglia
MeSH
Alzheimer Disease

path(MESH:"Alzheimer Disease") positiveCorrelation m(HGNC:MIR155) View Subject | View Object

Upregulation of several NF-κB regulated miRNAs such as miRNA-9, miRNA-34a, miRNA-125b, miRNA-146a, miRNA-155 and miRNA-339 5p have been observed in stressed primary human neuronalglial cells and in postmortem AD brain tissues PubMed:25652642

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Brain
MeSH
Neuroglia
MeSH
Alzheimer Disease

path(MESH:"Alzheimer Disease") positiveCorrelation m(HGNC:MIR339) View Subject | View Object

Upregulation of several NF-κB regulated miRNAs such as miRNA-9, miRNA-34a, miRNA-125b, miRNA-146a, miRNA-155 and miRNA-339 5p have been observed in stressed primary human neuronalglial cells and in postmortem AD brain tissues PubMed:25652642

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Brain
MeSH
Neuroglia
MeSH
Alzheimer Disease

path(MESH:"Alzheimer Disease") positiveCorrelation p(HGNC:MAPT, pmod(HBP:hyperphosphorylation)) View Subject | View Object

Moreover, pathological deposition of hyperphosphorylated MAP-tau (MAPT), which is the hallmark of several neurodegenerative disorders such as AD and frontotemporal dementia (FTD), has been described in elderly subjects with schizophrenia PubMed:30061532

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About

BEL Commons is developed and maintained in an academic capacity by Charles Tapley Hoyt and Daniel Domingo-Fernández at the Fraunhofer SCAI Department of Bioinformatics with support from the IMI project, AETIONOMY. It is built on top of PyBEL, an open source project. Please feel free to contact us here to give us feedback or report any issues. Also, see our Publishing Notes and Data Protection information.

If you find BEL Commons useful in your work, please consider citing: Hoyt, C. T., Domingo-Fernández, D., & Hofmann-Apitius, M. (2018). BEL Commons: an environment for exploration and analysis of networks encoded in Biological Expression Language. Database, 2018(3), 1–11.