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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

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

albuquerque2009 v1.0.0

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

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

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

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

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

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

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

Tau oligomers and tau toxicity in neurodegenerative disease v1.0.0

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

Tau Biochemistry v1.2.5

Tau Biochemistry Section of NESTOR

Tau Modifications v1.9.5

Tau Modifications Sections of NESTOR

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Annotations
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

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

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

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

Annotations
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

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

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

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

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

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

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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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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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:
Annotations
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

Appears in Networks:
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Text Location
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

Appears in Networks:
Annotations
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

Appears in Networks:
Annotations
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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Annotations
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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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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

Appears in Networks:
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

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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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Annotations
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

Annotations
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

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

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

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

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

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

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

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