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a(CHEBI:"amyloid-beta")

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Entity

Name
amyloid-beta
Namespace
chebi
Namespace Version
20180906
Namespace URL
https://raw.githubusercontent.com/pharmacome/terminology/b46b65c3da259b6e86026514dfececab7c22a11b/external/chebi-names.belns

Appears in Networks 52

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

A role for APP in Wnt signalling links synapse loss with β-amyloid production. v1.0.0

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

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

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

Effects of peptides derived from BACE1 catalytic domain on APP processing v1.0.0

APP processing in Alzheimer's disease v1.0.1

APP processing in Alzheimer's disease

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

albuquerque2009 v1.0.0

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

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

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

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

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

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

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

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

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

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

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

Cholinergic system during the progression of Alzheimer’s disease: therapeutic implications v1.0.0

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

The alpha7 nicotinic receptor agonist 4OH-GTS-21 protects axotomized septohippocampal cholinergic neurons in wild type but not amyloid-overexpressing transgenic mice v1.0.0

Chaperoning α7 neuronal nicotinic acetylcholine receptors v1.0.0

Naturally-expressed nicotinic acetylcholine receptor subtypes v1.0.0

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

The Biology of Proteostasis in Aging and Disease v1.0.0

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

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

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

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

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

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

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

Tau Modifications v1.9.5

Tau Modifications Sections of NESTOR

Inflammasome activation and innate immunity in Alzheimer’s disease v1.0.2

Activation and regulation of the inflammasomes v1.0.0

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

Inflammasome Involvement in Alzheimer’s Disease v1.0.0

Anatabine lowers Alzheimer's Aβ production in vitro and in vivo v1.0.0

Chronic Anatabine Treatment Reduces Alzheimer ’ s Disease (AD)-Like Pathology and Improves Socio-Behavioral Deficits in a Transgenic Mouse Model of AD v1.0.0

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

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

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

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

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

The Spleen Tyrosine Kinase (Syk) Regulates Alzheimer Amyloid-β Production and Tau Hyperphosphorylation* v1.0.0

Caenorhabditis elegans models of tauopathy v1.0.0

Tau in physiology and pathology v1.0.0

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

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

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

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

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

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

mTOR-Related Brain Dysfunctions in Neuropsychiatric Disorders v1.0.0

In-Edges 423

tloc(a(CHEBI:"amyloid-beta"), fromLoc(MESH:Blood), toLoc(MESH:"Cerebrospinal Fluid")) regulates deg(a(CHEBI:"amyloid-beta")) View Subject | View Object

By contrast, the parenchyma of the CNS is devoid of lymphatic vasculature2; in the brain, removal of cellular debris and toxic molecules, such as amyloid-β peptides, is mediated by a combination of transcellular transport mechanisms across the blood−brain and blood−cerebrospinal fluid (CSF) barriers7–9, phagocytosis and digestion by resident microglia and recruited monocytes and/or macrophages10,11, as well as CSF influx and ISF efflux through a paravascular (glymphatic) route12–14 PubMed:30046111

Appears in Networks:
Annotations
Confidence
High
MeSH
Brain

act(a(HP:"interstitial fluid")) decreases a(CHEBI:"amyloid-beta") View Subject | View Object

The ageing-associated decrease in paravascular recirculation of CSF and ISF is thought to be responsible, at least in part, for the accumulation of amyloid-β in the brain parenchyma PubMed:30046111

Appears in Networks:
Annotations
Confidence
High
MeSH
Brain
MeSH
Parenchymal Tissue

complex(a(CHEBI:"amyloid-beta"), p(HGNC:CHRNB2)) hasComponent a(CHEBI:"amyloid-beta") View Subject | View Object

Appears in Networks:

act(a(MESH:"Lymphatic Vessels")) decreases a(CHEBI:"amyloid-beta") View Subject | View Object

However, 5xFAD mice with ablated meningeal lymphatic vessels demonstrated marked deposition of amyloid-β in the meninges (Fig. 3b), as well as macrophage recruitment to large amyloid-β aggregates (Fig. 3c) PubMed:30046111

Appears in Networks:
Annotations
Confidence
High
MeSH
Meninges

act(a(MESH:"Lymphatic Vessels")) negativeCorrelation a(CHEBI:"amyloid-beta") View Subject | View Object

Analysis of lymphoid and myeloid cell populations in the meninges (Extended Data Fig. 9d) demonstrated a significant increase in the number of macrophages upon lymphatic ablation compared to both control groups (Extended Data Fig. 9e), which might be correlated with increased amyloid-β deposition and inflammation in the meninges PubMed:30046111

Appears in Networks:
Annotations
Confidence
High
MeSH
Meninges

act(a(MESH:"Lymphatic Vessels")) decreases a(CHEBI:"amyloid-beta") View Subject | View Object

Notably, along with meningeal amyloid-β pathology, we observed an aggravation of brain amyloid-β burden in the hippocampi of 5xFAD mice with dysfunctional meningeal lymphatic vessels (Fig. 3d–g) PubMed:30046111

Appears in Networks:
Annotations
Confidence
High
MeSH
Hippocampus
MeSH
Meninges

act(a(MESH:"Lymphatic Vessels")) decreases a(CHEBI:"amyloid-beta") View Subject | View Object

A similar outcome was observed in J20 transgenic mice after a total of three months of meningeal lymphatic ablation (Extended Data Fig. 9f); amyloid-β aggregates had formed in the meninges (Extended Data Fig. 9g) and the amyloid-β plaque load in the hippocampi of these mice was significantly increased (Extended Data Fig. 9h–k) PubMed:30046111

Appears in Networks:
Annotations
Confidence
High
MeSH
Meninges

a(MESH:"Lymphatic Vessels") decreases a(CHEBI:"amyloid-beta") View Subject | View Object

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

Appears in Networks:
Annotations
Confidence
Medium
MeSH
Meninges
MeSH
Alzheimer Disease

a(MESH:Macrophages) regulates deg(a(CHEBI:"amyloid-beta")) View Subject | View Object

By contrast, the parenchyma of the CNS is devoid of lymphatic vasculature2; in the brain, removal of cellular debris and toxic molecules, such as amyloid-β peptides, is mediated by a combination of transcellular transport mechanisms across the blood−brain and blood−cerebrospinal fluid (CSF) barriers7–9, phagocytosis and digestion by resident microglia and recruited monocytes and/or macrophages10,11, as well as CSF influx and ISF efflux through a paravascular (glymphatic) route12–14 PubMed:30046111

Appears in Networks:
Annotations
Confidence
High
MeSH
Brain

a(MESH:Macrophages) association a(CHEBI:"amyloid-beta") View Subject | View Object

Macrophages in the dura of cases with Alzheimer’s disease were also found in close proximity to amyloid-β deposits (Fig. 3l) PubMed:30046111

Appears in Networks:
Annotations
Confidence
High
MeSH
Dura Mater
MeSH
Alzheimer Disease

a(MESH:Microglia) regulates deg(a(CHEBI:"amyloid-beta")) View Subject | View Object

By contrast, the parenchyma of the CNS is devoid of lymphatic vasculature2; in the brain, removal of cellular debris and toxic molecules, such as amyloid-β peptides, is mediated by a combination of transcellular transport mechanisms across the blood−brain and blood−cerebrospinal fluid (CSF) barriers7–9, phagocytosis and digestion by resident microglia and recruited monocytes and/or macrophages10,11, as well as CSF influx and ISF efflux through a paravascular (glymphatic) route12–14 PubMed:30046111

Appears in Networks:
Annotations
Confidence
High
MeSH
Brain

a(MESH:Monocytes) regulates deg(a(CHEBI:"amyloid-beta")) View Subject | View Object

By contrast, the parenchyma of the CNS is devoid of lymphatic vasculature2; in the brain, removal of cellular debris and toxic molecules, such as amyloid-β peptides, is mediated by a combination of transcellular transport mechanisms across the blood−brain and blood−cerebrospinal fluid (CSF) barriers7–9, phagocytosis and digestion by resident microglia and recruited monocytes and/or macrophages10,11, as well as CSF influx and ISF efflux through a paravascular (glymphatic) route12–14 PubMed:30046111

Appears in Networks:
Annotations
Confidence
High
MeSH
Brain

bp(GO:"cerebrospinal fluid circulation") decreases a(CHEBI:"amyloid-beta") View Subject | View Object

The ageing-associated decrease in paravascular recirculation of CSF and ISF is thought to be responsible, at least in part, for the accumulation of amyloid-β in the brain parenchyma PubMed:30046111

Appears in Networks:
Annotations
Confidence
High
MeSH
Brain
MeSH
Parenchymal Tissue

bp(GO:aging) increases a(CHEBI:"amyloid-beta") View Subject | View Object

The ageing-associated decrease in paravascular recirculation of CSF and ISF is thought to be responsible, at least in part, for the accumulation of amyloid-β in the brain parenchyma PubMed:30046111

Appears in Networks:
Annotations
Confidence
High
MeSH
Brain
MeSH
Parenchymal Tissue

bp(GO:phagocytosis) regulates deg(a(CHEBI:"amyloid-beta")) View Subject | View Object

By contrast, the parenchyma of the CNS is devoid of lymphatic vasculature2; in the brain, removal of cellular debris and toxic molecules, such as amyloid-β peptides, is mediated by a combination of transcellular transport mechanisms across the blood−brain and blood−cerebrospinal fluid (CSF) barriers7–9, phagocytosis and digestion by resident microglia and recruited monocytes and/or macrophages10,11, as well as CSF influx and ISF efflux through a paravascular (glymphatic) route12–14 PubMed:30046111

Appears in Networks:
Annotations
Confidence
High
MeSH
Brain

p(MGI:Vegfc) causesNoChange a(CHEBI:"amyloid-beta") View Subject | View Object

Moreover, viral expression of mVEGF-C did not significantly affect the diameter of meningeal lymphatic vessels, the level of amyloid-β in the CSF, or amyloid-β deposition in the hippocampus (Extended Data Fig. 8g–n) PubMed:30046111

Appears in Networks:
Annotations
Confidence
High
MeSH
Cerebrospinal Fluid
MeSH
Hippocampus
MeSH
Alzheimer Disease

bp(GO:"Wnt signaling pathway, planar cell polarity pathway") increases a(CHEBI:"amyloid-beta") View Subject | View Object

In cells expressing either wild-type or Swedish APP, the amount of Aβ produced was reduced in cells stimulated with Wnt3a, which promotes Wnt-βcatenin signalling, whereas Aβ production was enhanced in cells stimulated with Wnt5a, which promotes Wnt-PCP signalling (Fig. 2c). PubMed:30232325

Appears in Networks:
Annotations
Confidence
High

p(MGI:Aqp4) decreases a(CHEBI:"amyloid-beta") View Subject | View Object

Deletion of Aqp4 in transgenic mice with Alzheimer’s disease also resulted in increased amyloid-β plaque burden and exacerbated cognitive impairment PubMed:30046111

Appears in Networks:
Annotations
Confidence
High
MeSH
Alzheimer Disease

complex(a(CHEBI:"amyloid-beta"), p(MGI:Chrna7)) hasComponent a(CHEBI:"amyloid-beta") View Subject | View Object

Appears in Networks:

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

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

Appears in Networks:
Annotations
Confidence
Medium
MeSH
Brain
MeSH
Parenchymal Tissue

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

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

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

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

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

Appears in Networks:
Annotations
Confidence
Medium
MeSH
Meninges
MeSH
Alzheimer Disease

bp(GO:"canonical Wnt signaling pathway") decreases a(CHEBI:"amyloid-beta") View Subject | View Object

In cells expressing either wild-type or Swedish APP, the amount of Aβ produced was reduced in cells stimulated with Wnt3a, which promotes Wnt-βcatenin signalling, whereas Aβ production was enhanced in cells stimulated with Wnt5a, which promotes Wnt-PCP signalling (Fig. 2c). PubMed:30232325

Appears in Networks:
Annotations
Confidence
High

complex(a(CHEBI:"amyloid-beta"), p(RGD:Chrna7)) hasComponent a(CHEBI:"amyloid-beta") View Subject | View Object

Appears in Networks:

composite(a(CHEBI:"fasudil hydrochloride"), p(HGNC:DKK1)) causesNoChange a(CHEBI:"amyloid-beta") View Subject | View Object

Notably, in parallel with the protective effect of fasudil on synapses (Fig. 3e, f), treatment with fasudil reversed the stimulatory effects of Dkk1 on Aβ production (Fig. 3g). PubMed:30232325

Appears in Networks:
Annotations
Confidence
Medium

p(HGNC:BACE1, frag("67_78")) causesNoChange a(CHEBI:"amyloid-beta") View Subject | View Object

Neither, BI-1 nor, BI-3, nor any of the other peptides used in this study, induced any changes of full-length APP levels. They also did not affect the level of b-actin. PubMed:17293005

Appears in Networks:

p(HGNC:DKK1) increases a(CHEBI:"amyloid-beta") View Subject | View Object

In addition to causing a significant reduction in the numbers of dendritic spines, Dkk1 treatment also resulted a substantial increase in levels of all three Aβ species (Fig. 3g). PubMed:30232325

Appears in Networks:
Annotations
Confidence
Medium

composite(p(HGNC:APP), p(HGNC:LRP6)) decreases a(CHEBI:"amyloid-beta") View Subject | View Object

Co-expression of LRP6 with APP reduced the production of Aβ, while co-expression of Vangl2 with APP led to increased Aβ production (Fig. 2c). PubMed:30232325

Appears in Networks:
Annotations
Confidence
Medium

composite(p(HGNC:APP), p(HGNC:VANGL2)) increases a(CHEBI:"amyloid-beta") View Subject | View Object

Co-expression of LRP6 with APP reduced the production of Aβ, while co-expression of Vangl2 with APP led to increased Aβ production (Fig. 2c). PubMed:30232325

Appears in Networks:
Annotations
Confidence
Medium

p(HGNC:APP, var("p.Lys670Asn"), var("p.Met671Leu")) increases a(CHEBI:"amyloid-beta") View Subject | View Object

As expected, cells expressing the Swedish mutant form of APP695 produced much more Aβ than the control wildtype-expressing cells. PubMed:30232325

Appears in Networks:
Annotations
Confidence
High

act(p(HGNC:WNT3A)) decreases a(CHEBI:"amyloid-beta") View Subject | View Object

In cells expressing either wild-type or Swedish APP, the amount of Aβ produced was reduced in cells stimulated with Wnt3a, which promotes Wnt-βcatenin signalling, whereas Aβ production was enhanced in cells stimulated with Wnt5a, which promotes Wnt-PCP signalling (Fig. 2c). PubMed:30232325

Appears in Networks:
Annotations
Confidence
High

act(p(HGNC:WNT3A)) increases a(CHEBI:"amyloid-beta") View Subject | View Object

In cells expressing either wild-type or Swedish APP, the amount of Aβ produced was reduced in cells stimulated with Wnt3a, which promotes Wnt-βcatenin signalling, whereas Aβ production was enhanced in cells stimulated with Wnt5a, which promotes Wnt-PCP signalling (Fig. 2c). PubMed:30232325

Appears in Networks:
Annotations
Confidence
High

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

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

Appears in Networks:
Annotations
Confidence
Medium

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

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

Appears in Networks:
Annotations
Confidence
High

p(HGNC:APBA1) decreases a(CHEBI:"amyloid-beta") View Subject | View Object

Overexpression of Mint1, Mint2, or Fe65 causes reduction in Aβ generation and deposition in the brains of transgenic mice, strongly suggesting a physiological role for these adaptors in regulating APP processing in the nervous tis- sue (17). PubMed:18650430

Appears in Networks:
Annotations
Confidence
Medium

p(HGNC:APBA2) decreases a(CHEBI:"amyloid-beta") View Subject | View Object

Overexpression of Mint1, Mint2, or Fe65 causes reduction in Aβ generation and deposition in the brains of transgenic mice, strongly suggesting a physiological role for these adaptors in regulating APP processing in the nervous tis- sue (17). PubMed:18650430

Appears in Networks:
Annotations
Confidence
Medium

p(HGNC:APBB1) decreases a(CHEBI:"amyloid-beta") View Subject | View Object

Overexpression of Mint1, Mint2, or Fe65 causes reduction in Aβ generation and deposition in the brains of transgenic mice, strongly suggesting a physiological role for these adaptors in regulating APP processing in the nervous tis- sue (17). PubMed:18650430

Appears in Networks:
Annotations
Confidence
Medium

p(HGNC:SORL1) decreases a(CHEBI:"amyloid-beta") View Subject | View Object

Finally, the type I transmembrane protein SorLA/LR11 (a member of the VPS10p domain receptor fam- ily), which functionally interacts with cytosolic adaptors GGA and PACS-1, attenuates Aβ production by acting as a Golgi/ TGN retention factor (22). PubMed:18650430

Appears in Networks:
Annotations
Confidence
High

p(HGNC:BACE1, frag("228_236")) causesNoChange a(CHEBI:"amyloid-beta") View Subject | View Object

Neither, BI-1 nor, BI-3, nor any of the other peptides used in this study, induced any changes of full-length APP levels. They also did not affect the level of b-actin. PubMed:17293005

Appears in Networks:

p(HGNC:BACE1, frag("230_235")) causesNoChange a(CHEBI:"amyloid-beta") View Subject | View Object

Neither, BI-1 nor, BI-3, nor any of the other peptides used in this study, induced any changes of full-length APP levels. They also did not affect the level of b-actin. PubMed:17293005

Appears in Networks:

p(HGNC:BACE1, frag("69_75")) causesNoChange a(CHEBI:"amyloid-beta") View Subject | View Object

Neither, BI-1 nor, BI-3, nor any of the other peptides used in this study, induced any changes of full-length APP levels. They also did not affect the level of b-actin. PubMed:17293005

Appears in Networks:

a(CHEBI:"phorbol ester") association a(CHEBI:"amyloid-beta") View Subject | View Object

Indeed, phorbol ester’s effect on sAPPalpha secretion and Abeta generation though activation of protein kinase C (PKC) has been known for a long time [201-203] PubMed:21214928

Appears in Networks:
Annotations
MeSH
Cell Membrane
Confidence
High
MeSH
Hippocampus
MeSH
Down Syndrome

p(HGNC:APP) increases a(CHEBI:"amyloid-beta") View Subject | View Object

Abeta is generated from b-amyloid precursor protein (APP) through sequential cleavages first by beta-secretase and then by gamma-secretase complex PubMed:21214928

Appears in Networks:
Annotations
Confidence
Medium

a(CHEBI:estrogen) decreases a(CHEBI:"amyloid-beta") View Subject | View Object

We have found that estrogen may reduce Abeta levels by stimulating the alpha-secretase pathway and thereby inhibit Abeta generation PubMed:21214928

Appears in Networks:
Annotations
MeSH
Cell Membrane
Confidence
High
MeSH
Hippocampus
MeSH
Down Syndrome

complex(a(CHEBI:"amyloid-beta"), p(HGNC:DNM1)) hasComponent a(CHEBI:"amyloid-beta") View Subject | View Object

Appears in Networks:

a(MESH:"Potassium Channels") association a(CHEBI:"amyloid-beta") View Subject | View Object

Picomolar levels of Abeta can also rescue neuronal cell death induced by inhibition of Abeta generation (by exposure to inhibitors of beta- or gamma-scretases) [160], possibly through regulating the potassium ion channel expression, hence affecting neuronal excitability [161] PubMed:21214928

Appears in Networks:
Annotations
MeSH
Endosomes
Confidence
Low
MeSH
Hippocampus
MeSH
Down Syndrome

a(MESH:"Receptors, N-Methyl-D-Aspartate") increases a(CHEBI:"amyloid-beta") View Subject | View Object

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

Appears in Networks:
Annotations
Confidence
Medium

bp(GO:"ERK1 and ERK2 cascade") association a(CHEBI:"amyloid-beta") View Subject | View Object

Intraneuronal Abeta can also impair amygdala-dependent emotional responses by affecting the ERK/MAPK signaling pathway [153] PubMed:21214928

Appears in Networks:
Annotations
MeSH
Endosomes
Confidence
High
MeSH
Neurons
MeSH
Down Syndrome

bp(GO:"MAPK cascade") association a(CHEBI:"amyloid-beta") View Subject | View Object

Intraneuronal Abeta can also impair amygdala-dependent emotional responses by affecting the ERK/MAPK signaling pathway [153] PubMed:21214928

Appears in Networks:
Annotations
MeSH
Endosomes
Confidence
High
MeSH
Neurons
MeSH
Down Syndrome

bp(MESH:"Synaptic Transmission") association a(CHEBI:"amyloid-beta") View Subject | View Object

Although excessive Abeta causes synaptic dysfunction and synapse loss [142], low levels of Abeta increase hippocampal longterm potentiation and enhances memory, indicating a novel positive, modulatory role on neurotransmission and memory [158,159] PubMed:21214928

Appears in Networks:
Annotations
MeSH
Endosomes
Confidence
High
MeSH
Neurons
MeSH
Down Syndrome

complex(a(CHEBI:"amyloid-beta"), p(HGNC:APP)) hasComponent a(CHEBI:"amyloid-beta") View Subject | View Object

Appears in Networks:

complex(a(HBP:HBP00024), complex(FPLX:"Gamma_secretase"), p(HGNC:GSAP)) increases a(CHEBI:"amyloid-beta") View Subject | View Object

Recently, a novel gamma-secretase activating protein (GSAP) was identified and GSAP was found to selectively increase Abeta production through interaction with both gamma-secretase and the APP CTF substrate [117] PubMed:21214928

Appears in Networks:
Annotations
MeSH
Endosomes
Confidence
Medium
MeSH
Neurons

complex(p(HGNC:APBA1), p(HGNC:APP)) association a(CHEBI:"amyloid-beta") View Subject | View Object

APP interaction with mint proteins has been shown to affect APP processing by stabilizing cellular APP, altering both sAPPalpha and Abeta generation and secretion [166] PubMed:21214928

Appears in Networks:
Annotations
MeSH
Endosomes
Confidence
High
MeSH
Hippocampus
MeSH
Down Syndrome

complex(p(HGNC:APBA1), p(HGNC:APP)) association sec(a(CHEBI:"amyloid-beta")) View Subject | View Object

APP interaction with mint proteins has been shown to affect APP processing by stabilizing cellular APP, altering both sAPPalpha and Abeta generation and secretion [166] PubMed:21214928

Appears in Networks:
Annotations
MeSH
Endosomes
Confidence
High
MeSH
Hippocampus
MeSH
Down Syndrome

complex(p(HGNC:APBA2), p(HGNC:APP)) association a(CHEBI:"amyloid-beta") View Subject | View Object

APP interaction with mint proteins has been shown to affect APP processing by stabilizing cellular APP, altering both sAPPalpha and Abeta generation and secretion [166] PubMed:21214928

Appears in Networks:
Annotations
MeSH
Endosomes
Confidence
High
MeSH
Hippocampus
MeSH
Down Syndrome

complex(p(HGNC:APBA2), p(HGNC:APP)) association sec(a(CHEBI:"amyloid-beta")) View Subject | View Object

APP interaction with mint proteins has been shown to affect APP processing by stabilizing cellular APP, altering both sAPPalpha and Abeta generation and secretion [166] PubMed:21214928

Appears in Networks:
Annotations
MeSH
Endosomes
Confidence
High
MeSH
Hippocampus
MeSH
Down Syndrome

complex(p(HGNC:APBA3), p(HGNC:APP)) association a(CHEBI:"amyloid-beta") View Subject | View Object

APP interaction with mint proteins has been shown to affect APP processing by stabilizing cellular APP, altering both sAPPalpha and Abeta generation and secretion [166] PubMed:21214928

Appears in Networks:
Annotations
MeSH
Endosomes
Confidence
High
MeSH
Hippocampus
MeSH
Down Syndrome

complex(p(HGNC:APBA3), p(HGNC:APP)) association sec(a(CHEBI:"amyloid-beta")) View Subject | View Object

APP interaction with mint proteins has been shown to affect APP processing by stabilizing cellular APP, altering both sAPPalpha and Abeta generation and secretion [166] PubMed:21214928

Appears in Networks:
Annotations
MeSH
Endosomes
Confidence
High
MeSH
Hippocampus
MeSH
Down Syndrome

complex(p(HGNC:APP), p(HGNC:LRP1)) increases a(CHEBI:"amyloid-beta") View Subject | View Object

Antagonizing the extracellular interaction between cell-surface APP and LRP increased the level of cell surface APP while decreasing Abeta generation [187] PubMed:21214928

Appears in Networks:
Annotations
MeSH
Endosomes
Confidence
Medium
MeSH
Hippocampus
MeSH
Down Syndrome

complex(p(HGNC:APP), p(HGNC:LRP1B)) decreases a(CHEBI:"amyloid-beta") View Subject | View Object

An LRP-related protein 1B (LRP1B) has a similar effect, binding APP at the plasma membrane, preventing APP internalization, and leading to decreased Abeta generation and increased sAPPalpha secretion [189] PubMed:21214928

Appears in Networks:
Annotations
MeSH
Cell Membrane
Confidence
High
MeSH
Hippocampus
MeSH
Down Syndrome

p(HGNC:ADAM10) decreases a(CHEBI:"amyloid-beta") View Subject | View Object

Alternatively, APP can be cleaved by alpha-secretase within the Abeta domain to release soluble APPa and preclude Abeta generation PubMed:21214928

Appears in Networks:
Annotations
Confidence
Medium

p(HGNC:ADAM10) decreases a(CHEBI:"amyloid-beta") View Subject | View Object

Cleavage of APP by alpha-secretase precludes Abeta generation as the cleavage site is within the Abeta domain (at the Lys16- Leu17 bond), and releases a large soluble ectodomain of APP called sAPPalpha PubMed:21214928

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Annotations
Confidence
Medium
MeSH
Neurons

p(HGNC:PRKACA) decreases a(CHEBI:"amyloid-beta") View Subject | View Object

In support of this, protein kinase A (PKA) has similar effects on reducing Abeta generation and stimulating the budding of APP-containing vesicles from the TGN [207] PubMed:21214928

Appears in Networks:
Annotations
MeSH
Cell Membrane
Confidence
High
MeSH
Hippocampus
MeSH
Down Syndrome

p(HGNC:BSG) decreases a(CHEBI:"amyloid-beta") View Subject | View Object

Downregulation of CD147 increases Abeta production but its overexpression has no effect on Abeta generation [113] PubMed:21214928

Appears in Networks:
Annotations
MeSH
Endosomes
Confidence
Low
MeSH
Neurons

p(HGNC:BSG) causesNoChange a(CHEBI:"amyloid-beta") View Subject | View Object

Downregulation of CD147 increases Abeta production but its overexpression has no effect on Abeta generation [113] PubMed:21214928

Appears in Networks:
Annotations
MeSH
Endosomes
Confidence
Low
MeSH
Neurons

p(HGNC:CTSB) increases a(CHEBI:"amyloid-beta") View Subject | View Object

Inhibition of cathepsin B has been found to reduce Abeta production both in vivo and in vitro [92,93] PubMed:21214928

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Annotations
MeSH
Endosomes
Confidence
High
MeSH
Neurons

p(HGNC:PRKCA) decreases a(CHEBI:"amyloid-beta") View Subject | View Object

PKC stimulates sAPPalpha secretion, reducing Abeta levels, even when the phosphorylation sites on APP are mutated or the entire cytoplasmic domain is deleted [204] PubMed:21214928

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Annotations
MeSH
Cell Membrane
Confidence
High
MeSH
Hippocampus
MeSH
Down Syndrome

p(HGNC:RAB11A) decreases a(CHEBI:"amyloid-beta") View Subject | View Object

Additionally, estrogen has been found to facilitate binding of Rab11 to the TGN membrane and a dominant negative Rab11 mutant abolishes the estrogen-regulated change in APP trafficking, leading to increased Abeta formation [197] PubMed:21214928

Appears in Networks:
Annotations
MeSH
Cell Membrane
Confidence
High
MeSH
Hippocampus
MeSH
Down Syndrome

p(HGNC:SORL1) decreases a(CHEBI:"amyloid-beta") View Subject | View Object

Recently it was found that SorLA/ LR11 overexpression redistributed APP to the Golgi, decreasing Abeta generation, while SorLA/LR11 knockout mice have increased levels of Abeta, as found in AD patients [182] PubMed:21214928

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Annotations
MeSH
Endosomes
Confidence
High
MeSH
Hippocampus
MeSH
Down Syndrome

p(HGNC:TMED10) regulates a(CHEBI:"amyloid-beta") View Subject | View Object

However, another study failed to confirm the binding of TMP23/p21 to gamma-secretase, but rather suggested that TMP21/p23, which belongs to the p24 cargo family involved in vesicular trafficking regulation, influences APP trafficking and thus Abeta generation [116] PubMed:21214928

Appears in Networks:
Annotations
MeSH
Endosomes
Confidence
High
MeSH
Neurons

rxn(reactants(a(HBP:HBP00024)), products(a(CHEBI:"amyloid-beta"), a(HBP:HBP00072))) hasProduct a(CHEBI:"amyloid-beta") View Subject | View Object

Appears in Networks:

rxn(reactants(p(HGNC:APP)), products(a(CHEBI:"amyloid-beta"))) hasProduct a(CHEBI:"amyloid-beta") View Subject | View Object

Appears in Networks:

p(HGNC:APP) increases a(CHEBI:"amyloid-beta") View Subject | View Object

Cloning of the complementary DNA (cDNA) of Abeta revealed that Abeta is derived from a larger precursor protein (Tanzi et al. 1987) PubMed:22122372

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

complex(p(HBP:HBP00071), p(HGNC:APBA1)) decreases a(CHEBI:"amyloid-beta") View Subject | View Object

As an adaptor protein involved in protein sorting and trafficking, X11 has been suggested as affecting APP trafficking/metabolism by interacting with AICD, leading to reduced Abeta production PubMed:22122372

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Annotations
Confidence
High
MeSH
Neurons

p(HGNC:ADAM10) decreases a(CHEBI:"amyloid-beta") View Subject | View Object

Moderate neuronal over-expression of human ADAM10 increases sAPP-alpha production while reducing Abeta generation/ plaque formation in mice carrying the human APP V717I mutation, while expression of a catalytically-inactive form of the ADAM10 mutation increases the size and number of amyloid plaques in mouse brains (Postina et al. 2004) PubMed:22122372

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Annotations
Confidence
High
MeSH
Neurons

p(HGNC:BACE1) increases a(CHEBI:"amyloid-beta") View Subject | View Object

Knocking out the BACE1 gene prevents Abeta generation and completely abolishes Abeta pathology in mice expressing the Swedish mutation of human APP (Cai et al. 2001; Luo et al. 2001; Roberds et al. 2001; Ohno et al. 2004; Laird et al. 2005) PubMed:22122372

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Annotations
Confidence
High
MeSH
Neurons

p(HGNC:CTSB) increases deg(a(CHEBI:"amyloid-beta")) View Subject | View Object

However, recent studies suggest that Cathepsin B can degrade Abeta into harmless fragments PubMed:22122372

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Annotations
Confidence
High
MeSH
Neurons

act(p(HGNC:CHRNA7)) increases a(CHEBI:"amyloid-beta", loc(GO:intracellular)) View Subject | View Object

It is noteworthy that the alpha7 nAChR activity increases intracellular accumulation of Abeta in neurons (336), and Abeta peptides, in addition to modulating nAChR activity, downregulate the expression of nAChRs (197). PubMed:19126755

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Annotations
MeSH
Neurons
Text Location
Review

a(CHEBI:estradiol) decreases act(a(CHEBI:"amyloid-beta")) View Subject | View Object

In support of this notion, beta-estradiol protects PC12 cells from amyloid toxicity, and this is prevented when alpha7 nAChRs are blocked with methyllycaconitine (Svensson and Nordberg, 1999). PubMed:19293145

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Annotations
Experimental Factor Ontology (EFO)
PC12

a(CHEBI:estrogen) decreases act(a(CHEBI:"amyloid-beta")) View Subject | View Object

ApoE-epsilon4, but not ApoE-epsilon3, disrupts carbachol-stimulated phosphoinositol (PI) hydrolysis and so does Abeta and Abeta/ApoE-epsilon4 complexes in SH-SY5Y cells (Cedazo- Mínguez and Cowburn, 2001). The effect of Abeta and its ApoE complex on PI hydrolysis were blocked by estrogen, and this disruption was itself blocked by wortmannin, suggesting that PI3K mediates estrogen’s effect on PI hydrolysis. PubMed:19293145

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Annotations
Experimental Factor Ontology (EFO)
SH-SY5Y

complex(a(CHEBI:"amyloid-beta"), p(HGNC:CHRNA7)) hasComponent a(CHEBI:"amyloid-beta") View Subject | View Object

Appears in Networks:

a(CHEBI:genistein) decreases act(a(CHEBI:"amyloid-beta")) View Subject | View Object

Genistein, a phytoestrogen, protects SH-SY5Y cells (Bang et al., 2004) as well as cultured hippocampal neurons (Zeng et al., 2004) from Abeta toxicity. However, in addition to its action on estrogen receptors, genistein is also a general tyrosine kinase inhibitor that protects cultured neurons from L-glutamate toxicity (Kajta et al., 2007). PubMed:19293145

Appears in Networks:
Annotations
Experimental Factor Ontology (EFO)
SH-SY5Y

a(HBP:"amyloid-beta fibrils") isA a(CHEBI:"amyloid-beta") View Subject | View Object

Appears in Networks:

a(HBP:"amyloid-beta oligomers") isA a(CHEBI:"amyloid-beta") View Subject | View Object

Appears in Networks:

a(HBP:"sAPP-beta") decreases act(a(CHEBI:"amyloid-beta")) View Subject | View Object

Nicotine stimulates the secretion of betaAPP, which is trophic and neuroprotective against Abeta, from PC12 cells through an alpha7 and calcium-dependent pathway (Kim et al., 1997) as well as increasing the secretion of soluble APP and lowering the Abeta-containing sAPP-gamma in rats (Lahiri et al., 2002), again through nAChR-dependent mechanisms. Galantamine, a nAChR potentiator and AChE inhibitor, also increases the secretion of sAPP from human SH-SY5Y neuroblastoma cells (Lenzken et al., 2007) through the activation of nAChRs. It therefore seems that activation of nAChRs shifts the balance of APP processing away from beta-amyloidogenic to soluble APP production. PubMed:19293145

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Annotations
Experimental Factor Ontology (EFO)
PC12

act(a(MESH:"Cholinesterase Inhibitors")) decreases act(a(CHEBI:"amyloid-beta")) View Subject | View Object

Likewise, blocking the PI3K-AKT pathway inhibits the protective effects of AChE inhibitors on neuroblastoma cells or neuronal cells against Abeta (Arias et al., 2005) or L-glutamate neurotoxicity (Takada-Takatori et al., 2006). In all these studies, protection was also inhibited by nAChR blockers, suggesting that these effects are mediated by nAChRs. PubMed:19293145

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Annotations
MeSH
Neurons

a(MESH:Bungarotoxins) decreases act(a(CHEBI:"amyloid-beta")) View Subject | View Object

It is noteworthy that this internalization was blocked by alpha-bungarotoxin, which may indicate that alpha-bungarotoxin either inhibits binding of Abeta to the alpha7 receptor (and therefore that Abeta toxicity results from binding of Abeta to alpha7 nAChRs) or directly inhibits alpha7 nAChR internalization. PubMed:19293145

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bp(GO:"MAPK cascade") increases a(CHEBI:"amyloid-beta") View Subject | View Object

Nicotine also activates ERK in non-neuronal cells such as pancreatic acinar cells (Chowdhury et al., 2007) and vascular smooth muscle cells (Kanda and Watanabe, 2007), although it is not known in those cases which nAChR subtypes are involved. In the cortex and hippocampus of mice, nicotine’s inhibition of MAPK (shown by RNAi reduction of alpha7 expression to be alpha7-dependent) prevents activation of nuclear factor- kappaB and c-Myc, also thereby reducing the activity of inducible nitric-oxide synthetase and NO production and decreasing Abeta production (Liu et al., 2007). PubMed:19293145

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Annotations
Cell Ontology (CL)
pancreatic acinar cell
Cell Ontology (CL)
vascular associated smooth muscle cell

bp(GO:"calcium-mediated signaling") association act(a(CHEBI:"amyloid-beta")) View Subject | View Object

Calcium signaling pathways are involved both in the toxic action of Abeta and in the protection against that toxicity offered by nicotinic ligands. Given that alpha7 homomeric nAChRs are much more permeable to calcium ions than are most other nAChRs (Bertrand et al., 1993), it is to be expected that nicotinic neuroprotection mediated by nAChRs, notably alpha7, would depend upon the activation of calcium signaling pathways. ABT-418 is a nicotinic agonist that protects primary rat cortical neurons from glutamate toxicity through its activation of alpha7 nAChRs, and this is blocked when calcium is removed from the extracellular medium (Donnelly-Roberts et al., 1996). PubMed:19293145

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bp(GO:"choline transport") association a(CHEBI:"amyloid-beta") View Subject | View Object

For instance, in Abeta-overexpressing mice (PDAPP derived from a heterogeneous background comprising the strains C57BL/6J, DBA/2J, and Swiss-Webster), Abeta seems to target the high-affinity choline transporter (Bales et al., 2006). PubMed:19293145

Appears in Networks:

bp(GO:"synaptic transmission, cholinergic") association a(CHEBI:"amyloid-beta") View Subject | View Object

There is abundant evidence that Abeta also affects cholinergic signaling in the brain. Recent studies indicate that brain nAChRs are not only affected by Abeta but can also initiate signaling pathways that protect against Abeta toxicity (Kihara et al., 1997b; Takada et al., 2003; Arias et al., 2005; Akaike, 2006; Meunier et al., 2006; Dineley, 2007; Liu et al., 2007). PubMed:19293145

Appears in Networks:
Annotations
MeSH
Brain

bp(GO:"synaptic transmission, cholinergic") association a(CHEBI:"amyloid-beta") View Subject | View Object

Consequently, there is mounting evidence that Abeta affects cholinergic signaling independent of its cytotoxic action. For example, Abeta blocks long-term potentiation, a cellular correlate of learning, through activation of JNK and p38MAPK (Wang et al., 2004). PubMed:19293145

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p(HGNC:CHRNA7) positiveCorrelation a(CHEBI:"amyloid-beta") View Subject | View Object

In addition, not only have alpha7 nAChRs been found colocalized with plaques (Wang et al., 2000b) but alpha7 and alpha4 subunits are also positively correlated with neurons that accumulate Abeta (Wevers et al., 1999). PubMed:19293145

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Annotations
MeSH
Neurons

p(HGNC:CHRNA7) decreases act(a(CHEBI:"amyloid-beta")) View Subject | View Object

In SHSY5Y cells, RNA interference (RNAi) knockdown of alpha7 enhanced Abeta toxicity (Qi et al., 2007), and alpha7 antagonists, but not alpha4beta2 antagonists, block galantamine protection of cultured rat neurons (Kihara et al., 2004). Donepezil protects cultured rat cortical neurons against Abeta toxicity through both alpha7 and non-alpha7 nAChRs (Takada et al., 2003). It is therefore likely that alpha7 nAChRs are the primary mediators of nicotine neuroprotection, but in some cells, non-alpha7 subtypes are also likely to contribute. PubMed:19293145

Appears in Networks:

p(HGNC:CHRNA7) increases a(CHEBI:"amyloid-beta") View Subject | View Object

An indication that nAChRs may play a role in Abeta internalization comes from a close inspection of cholinergic neurons in brains from patients with AD, which revealed that neurons with high expression levels of alpha7 also contained large amounts of intracellular Abeta (Nagele et al., 2002). Addition of Abeta to the culture medium of neuroblastoma cells overexpressing alpha7 results in more Abeta internalization than in control cells with lower levels of alpha7 expression (Nagele et al., 2002). PubMed:19293145

Appears in Networks:
Annotations
MeSH
Brain
MeSH
Neurons
MeSH
Alzheimer Disease

p(HGNC:CHRNA7) association a(CHEBI:"amyloid-beta") View Subject | View Object

In contrast, Small et al. (2007) found no displacement of alpha-BTX from SH-SY5Y cells (a cell line very closely related to that used by Wang et al.) by either amyloid or methyllycaconitine. Wang et al. (2000b) also showed similar staining of human AD cortical neurons by alpha7 and Abeta antibodies in double immunofluorescence, suggesting that in human cortical neurons, alpha7 and Abeta are closely associated, although such an approach does not prove direct binding. However another study (Small et al., 2007) showed no displacement of labeled alpha-bungarotoxin from cell lines expressing rat alpha7 nAChRs. PubMed:19293145

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Annotations
Experimental Factor Ontology (EFO)
SH-SY5Y

p(HGNC:CHRNA4) positiveCorrelation a(CHEBI:"amyloid-beta") View Subject | View Object

In addition, not only have alpha7 nAChRs been found colocalized with plaques (Wang et al., 2000b) but alpha7 and alpha4 subunits are also positively correlated with neurons that accumulate Abeta (Wevers et al., 1999). PubMed:19293145

Appears in Networks:
Annotations
MeSH
Neurons

p(HGNCGENEFAMILY:"Cholinergic receptors nicotinic subunits") association a(CHEBI:"amyloid-beta") View Subject | View Object

There is abundant evidence that Abeta also affects cholinergic signaling in the brain. Recent studies indicate that brain nAChRs are not only affected by Abeta but can also initiate signaling pathways that protect against Abeta toxicity (Kihara et al., 1997b; Takada et al., 2003; Arias et al., 2005; Akaike, 2006; Meunier et al., 2006; Dineley, 2007; Liu et al., 2007). PubMed:19293145

Appears in Networks:
Annotations
MeSH
Brain

p(HGNCGENEFAMILY:"Cholinergic receptors nicotinic subunits") association a(CHEBI:"amyloid-beta") View Subject | View Object

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

Appears in Networks:

p(HGNCGENEFAMILY:"Cholinergic receptors nicotinic subunits") regulates sec(a(CHEBI:"amyloid-beta")) View Subject | View Object

In addition to Abeta acting upon nAChRs, nAChRs in turn regulate Abeta secretion. Nicotine or epibatidine applied to the human SHEP1 cell line stably transfected with human alpha4beta2 nAChRs and human APP decreases the secretion and intracellular accumulation of Abeta without significantly affecting the APP mRNA, suggesting that these effects are post-translational (Nie et al., 2007). PubMed:19293145

Appears in Networks:

p(HGNCGENEFAMILY:"Cholinergic receptors nicotinic subunits") regulates act(a(CHEBI:"amyloid-beta")) View Subject | View Object

Thus, it seems that nAChRs may play a role in mediating Abeta toxicity through synergistic mechanisms; in addition to possible direct interactions (binding), nAChRs may also result in accelerated cell death through enhancing intracellular Abeta accumulation. PubMed:19293145

Appears in Networks:

act(p(HGNCGENEFAMILY:"Cholinergic receptors nicotinic subunits")) association a(CHEBI:"amyloid-beta") View Subject | View Object

Although there is abundant evidence that Abeta can affect nAChR function, studies disagree as to whether Abeta is an antagonist or an agonist at nAChRs (these findings are summarized in Table 1). For example, Abeta has been reported to inhibit single-channel nicotinic receptor currents in rat hippocampal interneurons (Pettit et al., 2001) as well as currents recorded from human alpha7 receptors heterologously expressed in Xenopus laevis oocytes (Tozaki et al., 2002; Grassi et al., 2003; Pym et al., 2005). Abeta, however, activates a mutant (L250T) of the alpha7 receptor—this mutant conducts current in the desensitized state, indicating that Abeta may exert its antagonistic action through receptor desensitization (Grassi et al., 2003). PubMed:19293145

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p(HGNC:FYN) association act(a(CHEBI:"amyloid-beta")) View Subject | View Object

From these findings, it would seem that FYN plays a neuroprotective role. However, FYN may also play a paradoxical role in Abeta toxicity. Indeed, Abeta activates both FYN and the PI3K cascade (Williamson et al., 2002), whereas germline knockout of FYN is neuroprotective in mice (Lambert et al., 1998; Chin et al., 2004). FYN knockout protects mature mouse neurons in organotypic central nervous system cultures (Lambert et al., 1998). PubMed:19293145

Appears in Networks:

composite(a(CHEBI:"amyloid-beta"), complex(p(HGNC:CHRNA3), p(HGNC:CHRNB2))) hasComponent a(CHEBI:"amyloid-beta") View Subject | View Object

Appears in Networks:

composite(a(CHEBI:"amyloid-beta"), p(HGNC:CHRNA7)) hasComponent a(CHEBI:"amyloid-beta") View Subject | View Object

Appears in Networks:

composite(a(CHEBI:"amyloid-beta"), p(MGI:Ache)) hasComponent a(CHEBI:"amyloid-beta") View Subject | View Object

Appears in Networks:

composite(a(CHEBI:nicotine), complex(p(HGNC:CHRNA4), p(HGNC:CHRNB2))) decreases sec(a(CHEBI:"amyloid-beta")) View Subject | View Object

In addition to Abeta acting upon nAChRs, nAChRs in turn regulate Abeta secretion. Nicotine or epibatidine applied to the human SHEP1 cell line stably transfected with human alpha4beta2 nAChRs and human APP decreases the secretion and intracellular accumulation of Abeta without significantly affecting the APP mRNA, suggesting that these effects are post-translational (Nie et al., 2007). PubMed:19293145

Appears in Networks:

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

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

Appears in Networks:

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

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

Appears in Networks:

a(MESH:"1-(1'-(2-methylbenzyl)-1,4'-bipiperidin-4-yl)-1H-benzo(d)imidazol-2-(3H)-one") decreases a(CHEBI:"amyloid-beta") View Subject | View Object

Moreover, additional pre-clinical studies with TBPB demonstrated efficacy in reducing antipsychotic-like behaviors and in reversing scopolamine-impaired acquisition of contextual fear.59 Studies in cell lines also demonstrated that TBPB promoted a non-amyloidogenic pathway and decreased Abeta production, indicating that M1 modulation may have efficacy in the treatment of both symptomatic and pathologic features of AD PubMed:24511233

Appears in Networks:

p(MGI:Chrm1) decreases act(a(CHEBI:"amyloid-beta")) View Subject | View Object

Finally, studies in mice exhibiting AD-like Abeta plaque pathologies found that deletion of M1 increased amyloidogenic processes, suggesting that M1 may play a role in regulating AD disease progression.51 PubMed:24511233

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Annotations
MeSH
Alzheimer Disease

p(HGNC:CHRNA7) positiveCorrelation a(CHEBI:"amyloid-beta") View Subject | View Object

This prospect was supported by the finding that α7 nAChRs were found in plaques (159), and α7 and α4 subunits positively correlated with neurons that accumulated Aβ and hyperphosphorylated tau in AD brain tissue (161). PubMed:17009926

Appears in Networks:
Annotations
Cell Ontology (CL)
neuron
MeSH
Brain
MeSH
Alzheimer Disease

p(HGNC:CHRNA4) positiveCorrelation a(CHEBI:"amyloid-beta") View Subject | View Object

This prospect was supported by the finding that α7 nAChRs were found in plaques (159), and α7 and α4 subunits positively correlated with neurons that accumulated Aβ and hyperphosphorylated tau in AD brain tissue (161). PubMed:17009926

Appears in Networks:
Annotations
Cell Ontology (CL)
neuron
MeSH
Brain
MeSH
Alzheimer Disease

p(HGNC:ACHE) increases a(CHEBI:"amyloid-beta") View Subject | View Object

In this work, kinetic analyses revealed that a structural motif in AChE (a hydrophobic sequence of 35 resides peptides) was able to promote amyloid formation and its incorporation into the growing Aβ-fibrils PubMed:26813123

Appears in Networks:

act(p(HGNC:CHRM1)) association act(a(CHEBI:"amyloid-beta")) View Subject | View Object

Interestingly, M1 receptor signaling affects several of AD major hallmarks, including cholinergic deficit, cognitive dysfunction, and tau and Aβ pathologies PubMed:26813123

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Annotations
MeSH
Alzheimer Disease

act(p(HGNC:CHRM2)) increases a(CHEBI:"amyloid-beta") View Subject | View Object

In addition, activation of M2 receptors can cause an increase in Aβ production PubMed:26813123

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Annotations
MeSH
Alzheimer Disease

a(CHEBI:cevimeline) decreases a(CHEBI:"amyloid-beta") View Subject | View Object

Moreover, AF102B administration decreased the total CSF Abeta levels by 22% in 14 of 19 AD patients without affecting sAPPalpha levels. However, AF102B has serious side effects including gastrointestinal symptoms, diaphoresis, confusion, diarrhea, and asthenia PubMed:24590577

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Annotations
MeSH
Cerebrospinal Fluid
MeSH
Alzheimer Disease

a(MESH:"(S)-2-ethyl-8-methyl-1-thia-4,8-diazaspiro(4.5)decan-3-one") decreases a(CHEBI:"amyloid-beta") View Subject | View Object

When APP/PS1/tau triple transgenic (3×Tg) AD mice are treated with the selective M1 mAChR agonist AF267B, the endogenous level of BACE1 decreases via an unclear mechanism, accompanied by a decreased Abeta level[77]. However, another study found that stimulation of M1 mAChR upregulates BACE1 levels in SK-SH-SY5Y cells via the PKC and MAPK signaling cascades[78]. We recently found that M1 mAChR directly interacts with BACE1 and mediates its proteasomal degradation[79]. These results suggest that M1 mAChR modulates BACE1 in a mixed manner. PubMed:24590577

Appears in Networks:

a(MESH:"1-(1'-(2-methylbenzyl)-1,4'-bipiperidin-4-yl)-1H-benzo(d)imidazol-2-(3H)-one") decreases a(CHEBI:"amyloid-beta") View Subject | View Object

Nevertheless, a compound developed later, TBPB, selectively activates M1 mAChR in cell lines and shows no agonist activity in any other mAChR subtype. Interestingly, TBPB also potentiates the NMDA-evoked current in hippocampal pyramidal neurons, which is considered to be important for the effect of M1 mAChR on improving cognition. In addition, TBPB shifts the processing of APP in the non-amyloidogenic direction and thereafter decreases neurotoxic Abeta production vitro[120]. PubMed:24590577

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Annotations
MeSH
Hippocampus
MeSH
Pyramidal Cells

a(MESH:"talsaclidine fumarate") decreases a(CHEBI:"amyloid-beta") View Subject | View Object

Another M1 mAChR-selective agonist, talsaclidine, enhances nonamyloidogenic processing of APP, resulting in increased sAPPalpha release from both a transfected human astrocytoma cell line and rat brain slices in a dose-dependent manner, as well as significantly decreasing CSF Abeta in AD patients[111]. However, talsaclidine at high doses had several side-effects such as sweating and salivation PubMed:24590577

Appears in Networks:
Annotations
MeSH
Cerebrospinal Fluid

complex(FPLX:"Gamma_secretase") increases a(CHEBI:"amyloid-beta") View Subject | View Object

Abeta, an important player in AD, is derived from beta-amyloid precursor protein (APP) through sequential cleavages by beta- and gamma-secretases: APP is cleaved by beta-secretase (BACE1) to generate the large secreted derivative sAPPbeta and the membrane-bound APP C-terminal fragment-beta; the latter can be further cleaved by gamma-secretase to generate Abeta and APP intracellular domain. Alternatively, APP can be cleaved by alpha-secretase within the Abeta domain, which precludes Abeta production and instead generates secreted sAPPalpha that has been shown to be neuroprotective PubMed:24590577

Appears in Networks:

act(p(HGNC:CHRM1)) decreases a(CHEBI:"amyloid-beta") View Subject | View Object

Interestingly, stimulation of M1 mAChR by agonists has been found to enhance sAPPalpha generation and reduce Abeta production[61-70]. Protein kinase C (PKC) is well-known to be activated upon stimulation of M1 mAChR. PKC may promote the activity of alpha-secretase[71] and the traffi cking of APP from the Golgi/ trans-Golgi network to the cell surface PubMed:24590577

Appears in Networks:

complex(p(FPLX:"G_protein"), p(HGNC:CHRM1)) decreases a(CHEBI:"amyloid-beta") View Subject | View Object

In fact, Abeta has been shown to induce the uncoupling of M1 mAChR from G-protein, antagonizing the function of M1 mAChR under the pathological conditions of AD[96, 97]. Such an uncoupling may result in decreased signal transduction, reduced levels of sAPPalpha, and increased production of Abeta, triggering a vicious cycle. PubMed:24590577

Appears in Networks:
Annotations
MeSH
Alzheimer Disease

a(CHEBI:nicotine) decreases a(CHEBI:"amyloid-beta") View Subject | View Object

Long-term nicotine administration elicited a reduction in Abeta deposits in blood vessel PubMed:25514383

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Annotations
MeSH
Blood Vessels
MeSH
Alzheimer Disease

a(HBP:"PTI-125") increases act(a(CHEBI:"amyloid-beta")) View Subject | View Object

A novel molecule called PTI-125 was used to interfere with the interaction of FLNA and alpha7. The treatment with PTI-125 prevents FLNA binding to alpha7 and as consequence reduces the affinity of Abeta for nAChRs, attenuating the toxic effect of Abeta (Wang et al., 2012) PubMed:25514383

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a(HBP:"S 24795") decreases a(CHEBI:"amyloid-beta") View Subject | View Object

Another molecule investigated was 2-[2-(4- bromophenyl)-2-oxoethyl]-1-methyl pyridinium (S 24795), a partial alpha7 nAChR agonist. When this molecule was applied to synaptosomal preparations from rat frontal cortex and post mortem human AD samples it was able to dissociate Abeta in a concentration dependent manner PubMed:25514383

Appears in Networks:
Annotations
MeSH
Alzheimer Disease

complex(a(CHEBI:"amyloid-beta"), a(MESH:"alpha7 Nicotinic Acetylcholine Receptor")) hasComponent a(CHEBI:"amyloid-beta") View Subject | View Object

Appears in Networks:

a(HBP:"alpha-7 beta-2 nAChR") negativeCorrelation act(a(CHEBI:"amyloid-beta")) View Subject | View Object

This class of receptors seems to be particularly sensitive to Abeta-induced toxicity (Khiroug et al., 2002; Liu et al.,2009, 2012) PubMed:25514383

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p(MGI:Chrna7) increases a(CHEBI:"amyloid-beta") View Subject | View Object

The authors postulated that the absence of alpha7 could prevent Abeta intracellular accumulation ameliorating the cognitive neuropathology and its phenotypic association (Dziewczapolski et al., 2009) PubMed:25514383

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MeSH
Alzheimer Disease

p(MGI:Chrna7) decreases a(CHEBI:"amyloid-beta") View Subject | View Object

In the hippocampus, it was shown that APP-alpha7KO mice had high levels of Abeta, although significantly less than APP mice, an effect which is not due to modification of the APP expression level,equivalent in the two lines PubMed:25514383

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MeSH
Hippocampus
MeSH
Alzheimer Disease

complex(a(CHEBI:"amyloid-beta"), a(HBP:"beta-2-containing nAChR")) hasComponent a(CHEBI:"amyloid-beta") View Subject | View Object

Appears in Networks:

complex(a(CHEBI:"amyloid-beta"), p(FPLX:CHRN)) hasComponent a(CHEBI:"amyloid-beta") View Subject | View Object

Appears in Networks:

complex(a(CHEBI:"amyloid-beta"), p(FPLX:CHRN), p(HGNC:FLNA)) hasComponent a(CHEBI:"amyloid-beta") View Subject | View Object

Appears in Networks:

composite(a(CHEBI:"amyloid-beta"), a(CHEBI:nicotine)) hasComponent a(CHEBI:"amyloid-beta") View Subject | View Object

Appears in Networks:

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

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

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MeSH
Alzheimer Disease

complex(a(CHEBI:"amyloid-beta"), p(MGI:Chrnb2)) hasComponent a(CHEBI:"amyloid-beta") View Subject | View Object

Appears in Networks:

p(MGI:Chrnb2) increases a(CHEBI:"amyloid-beta") View Subject | View Object

We observed intracellular Abeta staining in the polymorphic layer of the DG that was absent in GFP-beta2 (Fig. 8) PubMed:27522251

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MeSH
Dentate Gyrus

a(CHEBI:rosiglitazone) decreases a(CHEBI:"amyloid-beta") View Subject | View Object

These animals were treated with a low dose of rosiglitazone (3 mg/kg/ day) for 12 weeks and evaluated for plaque deposition and behavior. These animals displayed an approximate 50% decrease in amyloid deposition, a decrease in Ab oligomers, preservation of pre and postsynaptic proteins and the attenuation of cognitive deficits in the Morris water maze. PubMed:21718217

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Confidence
High

act(p(HGNC:NR1H3)) increases deg(a(CHEBI:"amyloid-beta")) View Subject | View Object

Recently, they have been shown to promote the degradation of the Ab peptides in the brain by activating genes responsible for reverse cholesterol transport [13]. PubMed:21718217

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Annotations
Confidence
High
MeSH
Microglia

act(p(HGNC:NR1H3)) increases deg(a(CHEBI:"amyloid-beta")) View Subject | View Object

LXR activation increased the ApoE particle size of all human ApoE isoforms, suggesting that activation of this pathways may enhance Ab clearance regardless of the ApoE allele expressed [13]. PubMed:21718217

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Annotations
Confidence
Medium

p(HGNC:APOE) increases deg(a(CHEBI:"amyloid-beta")) View Subject | View Object

They were able to show that the lipidation of ApoE enhanced the degradation of soluble species of Ab by neprilysin in the endolytic compartments of microglia as well as extracellularly through the actions of the insulindegrading enzyme (IDE) [13]. PubMed:21718217

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Confidence
High
MeSH
Microglia

act(p(HGNC:APOE)) increases deg(a(CHEBI:"amyloid-beta")) View Subject | View Object

LXR activation increased the ApoE particle size of all human ApoE isoforms, suggesting that activation of this pathways may enhance Ab clearance regardless of the ApoE allele expressed [13]. PubMed:21718217

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Annotations
Confidence
Medium

p(HGNC:IDE) increases deg(a(CHEBI:"amyloid-beta")) View Subject | View Object

They were able to show that the lipidation of ApoE enhanced the degradation of soluble species of Ab by neprilysin in the endolytic compartments of microglia as well as extracellularly through the actions of the insulindegrading enzyme (IDE) [13]. PubMed:21718217

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Annotations
Confidence
High

p(HGNC:MME) increases deg(a(CHEBI:"amyloid-beta")) View Subject | View Object

They were able to show that the lipidation of ApoE enhanced the degradation of soluble species of Ab by neprilysin in the endolytic compartments of microglia as well as extracellularly through the actions of the insulindegrading enzyme (IDE) [13]. PubMed:21718217

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Annotations
Confidence
High
MeSH
Microglia

act(p(HGNC:PPARG)) increases deg(a(CHEBI:"amyloid-beta")) View Subject | View Object

Recently, they have been shown to promote the degradation of the Ab peptides in the brain by activating genes responsible for reverse cholesterol transport [13]. PubMed:21718217

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Confidence
High
MeSH
Microglia

p(MGI:Abca1) decreases a(CHEBI:"amyloid-beta") View Subject | View Object

Conversely, overexpression of ABCA1 in a mouse model of AD was shown to decrease both soluble and fibrillar pools of Ab in 12-month-old mice and reduce plaque burden [53]. PubMed:21718217

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Confidence
Medium

a(MESH:D002800) decreases a(CHEBI:"amyloid-beta") View Subject | View Object

Recent studies report that anticholinesterase drugs reduce circulating Ab deposition in several dementia types, including AD [159]. Evidence from clinical trials [160], noninvasive functional imaging [161] and basic science research suggest that cholinesterase inhibitors might alter APP processing and therefore provide some degree of neuroprotection [162,163] PubMed:18986241

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Disease Ontology (DO)
Alzheimer's disease
MeSH
Cognitive Dysfunction

p(HGNC:NGFR) increases a(CHEBI:"amyloid-beta") View Subject | View Object

It is also important to note that TrkA reduces and p75NTR activates β-secretase strike (BACE) cleavage of the amyloid precursor protein (APP), which requires NGF binding and activation of the second messenger ceramide [66]. Aging may activate beta-amyloid (Ab) generation in the brain by ‘switching’ from TrkA to p75NTR, suggesting that NGF receptor balance is a molecular link between normal aging of the brain and AD in relation to amyloid processing. PubMed:18986241

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Disease Ontology (DO)
Alzheimer's disease
MeSH
Cognitive Dysfunction

act(p(HGNC:BACE1)) increases a(CHEBI:"amyloid-beta") View Subject | View Object

It is also important to note that TrkA reduces and p75NTR activates β-secretase strike (BACE) cleavage of the amyloid precursor protein (APP), which requires NGF binding and activation of the second messenger ceramide [66]. Aging may activate beta-amyloid (Ab) generation in the brain by ‘switching’ from TrkA to p75NTR, suggesting that NGF receptor balance is a molecular link between normal aging of the brain and AD in relation to amyloid processing. PubMed:18986241

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Disease Ontology (DO)
Alzheimer's disease
MeSH
Cognitive Dysfunction

act(p(HGNC:GAL)) decreases a(CHEBI:"amyloid-beta") View Subject | View Object

For example, the neuropeptide GAL, which functions via the interaction with three G protein-coupled receptors termed GALR1, GALR2 and GALR3, has multiple biological actions, including effects on cognition and neuroplasticity [15,146,147]. In the late [148–150] but not early [151] stage of AD, fibers within the basal forebrain containing the neuropeptide GAL thicken and hyperinnervate surviving CBF neurons. Although animal and cell-culture studies have shown that GAL plays a crucial role in the regulation of CBF neuron activity [152] and rescues cholinergic cells from amyloid toxicity [153], the molecular consequences of this unique plasticity response upon CBF neurons in AD remain unclear. Gene expression studies of cholinergic transcripts have shown that GAL hyperinnervated, but not nonhyperinnervated, CBF neurons display an upregulation of ChAT expression in AD compared to controls [126] PubMed:18986241

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Disease Ontology (DO)
Alzheimer's disease
MeSH
Basal Forebrain
MeSH
Cholinergic Neurons
MeSH
Cognitive Dysfunction

a(CHEBI:estrogen) decreases act(a(CHEBI:"amyloid-beta")) View Subject | View Object

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

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MeSH
Alzheimer Disease

a(HBP:"alpha-7-containing nAChR") regulates act(a(CHEBI:"amyloid-beta")) View Subject | View Object

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

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MeSH
Alzheimer Disease

a(HBP:"4-OH-GTS-21") causesNoChange a(CHEBI:"amyloid-beta") View Subject | View Object

The density of this deposition was not affected by 2 weeks of twice per day injections of 1 mg/kg 4OH-GTS-21 (275 deposits/section) or by FFX lesions (37±0.4 deposits/section) PubMed:17640819

Appears in Networks:

composite(p(MGI:App, var("p.Lys670Asn"), var("p.Met671Leu")), p(MGI:Psen1, var("p.Met146Leu"))) increases a(CHEBI:"amyloid-beta") View Subject | View Object

Nine-month-old APP/PS1 mice had significant 6E10- staining amyloid deposition (32±5 deposits/section) PubMed:17640819

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complex(a(CHEBI:"amyloid-beta"), a(HBP:"alpha-7 beta-2 nAChR")) hasComponent a(CHEBI:"amyloid-beta") View Subject | View Object

Appears in Networks:

complex(GO:"proteasome complex") increases deg(a(CHEBI:"amyloid-beta")) View Subject | View Object

It has been shown that Abeta can be degraded by the proteasome in cultured neurons and astrocytes, and reatment with the proteasome inhibitor lactacystin decreased viability of cells exposed to Abeta (Lopez Salon et al., 2003). PubMed:14556719

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Cell Ontology (CL)
astrocyte
Cell Ontology (CL)
neuron

composite(a(CHEBI:"amyloid-beta"), p(HGNC:MAPT, var("?"))) hasComponent a(CHEBI:"amyloid-beta") View Subject | View Object

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p(HGNC:PSEN1, var("?")) increases a(CHEBI:"amyloid-beta") View Subject | View Object

Finally, some patients express mutant presenilin proteins 1 and 2 (PS1 and PS2) that can change the processing of APP by altering gamma secretase activity, thereby promoting the generation of amyloidogenic Abeta (Hardy and Selkoe, 2002). PubMed:14556719

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p(HGNC:PSEN2, var("?")) increases a(CHEBI:"amyloid-beta") View Subject | View Object

Finally, some patients express mutant presenilin proteins 1 and 2 (PS1 and PS2) that can change the processing of APP by altering gamma secretase activity, thereby promoting the generation of amyloidogenic Abeta (Hardy and Selkoe, 2002). PubMed:14556719

Appears in Networks:

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

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

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a(CHEBI:metformin) decreases a(CHEBI:"amyloid-beta") View Subject | View Object

Moreover, reductions in levels of hyper phosphorylated tau and Aβ were seen in metformin- treated neurons 117,118 , while it blunted neuronal loss in a neurochemical lesion model of PD in mice 119 . PubMed:30116051

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MeSH
Dopaminergic Neurons

a(CHEBI:resveratrol) decreases a(CHEBI:"amyloid-beta") View Subject | View Object

The ‘anti-ageing’ agent resveratrol is thought to indi- rectly recruit AMPK via activation of calcium/calmodulin- dependent protein kinase kinase 2 (CAMKK2), which, acting in synergy with Ca 2+ , exerts its effects via Thr172 phosphorylation 113 . This action, among others (below), is involved in its reduction of Aβ levels in N2a cells and neurons 114 and the elimination of Aβ and Htt in animal models of AD and HD 114,115 . PubMed:30116051

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MeSH
Dopaminergic Neurons

a(CHEBI:tanespimycin) decreases a(CHEBI:"amyloid-beta") View Subject | View Object

The less cytotoxic analogue of geldanamycin, 17-AAG, has improved brain penetrance. It decreased Aβ levels 223 , improved memory 224 and lowered tau in transgenic AD mice 224 . 17-AAG also reduced α-synuclein oligomers in H4 cells 220 . PubMed:30116051

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MeSH
Alzheimer Disease

a(PUBCHEM:129688311) decreases a(CHEBI:"amyloid-beta") View Subject | View Object

Harnessing TFEB by 2-hydroxypropyl-β-cyclodextrin promoted clearance of proteolipid aggregates and α-syn- uclein in a cellular model of PD 195,204 .It also augmented the elimination of Aβ in a Tg19959/CRND8 mouse model of AD 173 . PubMed:30116051

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MeSH
Alzheimer Disease

act(p(HGNC:AQP4)) increases deg(a(CHEBI:"amyloid-beta")) View Subject | View Object

Activation of aquaporin 4 channels on perivascular astrocytes to aid the glymphatic elimination of cerebral Aβ and other toxic proteins is a potential strategy for stimulating clearance. PubMed:30116051

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p(HGNC:IDE) increases deg(a(CHEBI:"amyloid-beta")) View Subject | View Object

Aβ42 and amylin (a pancreas-derived, AD-associated protein found in brain) are substrates for degradation by IDE, which also irreversibly traps Aβ42 and α-synuclein, preventing their aggregation and promoting ALN and UPS elimination 259 . PubMed:30116051

Appears in Networks:

act(p(HGNC:MCOLN1)) decreases a(CHEBI:"amyloid-beta") View Subject | View Object

Fourth, activation of the lysosomal Ca 2+ channel mucol- ipin transient receptor potential channel 1 (TRPML1) with a synthetic agonist (ML-SA1) increased lysoso- mal Ca 2+ release, lowered pH and promoted Aβ clear- ance 191,192 . PubMed:30116051

Appears in Networks:

p(HGNC:PSEN1, var("p.Gly183Val")) causesNoChange a(CHEBI:"amyloid-beta") View Subject | View Object

A PSEN1 mutation causes a Pick’s disease phenotype including FTD tau pathology without deposition of Abeta [145]; some MAPT single nucleotide polymorphisms have also been linked to sporadic Parkinson’s disease (PD, [146]); PubMed:26751493

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a(CHEBI:"amyloid-beta polypeptide 40") isA a(CHEBI:"amyloid-beta") View Subject | View Object

Appears in Networks:

a(CHEBI:"amyloid-beta polypeptide 42") isA a(CHEBI:"amyloid-beta") View Subject | View Object

Appears in Networks:

a(HBP:"amyloid-beta polypeptide 38") isA a(CHEBI:"amyloid-beta") View Subject | View Object

Appears in Networks:

a(MESH:"Muscle, Smooth, Vascular") decreases a(CHEBI:"amyloid-beta") View Subject | View Object

Specifically, ISF Aβ can be taken up by microglia and astrocytes, whereas perivascular Aβ can be degraded by vascular smooth muscle cells, perivascular macrophages, and astrocytes PubMed:26195256

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a(MESH:Astrocytes) decreases a(CHEBI:"amyloid-beta", loc(MESH:"Extracellular Fluid")) View Subject | View Object

Specifically, ISF Aβ can be taken up by microglia and astrocytes, whereas perivascular Aβ can be degraded by vascular smooth muscle cells, perivascular macrophages, and astrocytes PubMed:26195256

Appears in Networks:

a(MESH:Insulin) increases a(CHEBI:"amyloid-beta") View Subject | View Object

Second, both Aβ and insulin are ligands that compete for degradation by insulin-degrading enzyme; thus, hyper- insulinaemia can reduce clearance of Aβ, which might partly explain the link between type 2 diabetes mellitus and AD. PubMed:26195256

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Annotations
MeSH
Hippocampus
MeSH
Temporal Lobe

a(MESH:Insulin) association a(CHEBI:"amyloid-beta") View Subject | View Object

In addition, insulin-degrading enzyme has been proposed to have a role in Aβ clearance through the BBB, which might explain why BBB clearance is sensitive to insulin.144 PubMed:26195256

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MeSH
Hippocampus
MeSH
Temporal Lobe

a(MESH:Microglia) decreases a(CHEBI:"amyloid-beta", loc(MESH:"Extracellular Fluid")) View Subject | View Object

Specifically, ISF Aβ can be taken up by microglia and astrocytes, whereas perivascular Aβ can be degraded by vascular smooth muscle cells, perivascular macrophages, and astrocytes PubMed:26195256

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bp(HBP:"perivascular drainage pathways") association a(CHEBI:"amyloid-beta") View Subject | View Object

Aβ is cleared along perivascular drainage pathways.83 In both AD44,160 and CAA44 (commonly associated with AD84), perivascular drainage of Aβ is impaired. PubMed:26195256

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MeSH
Hippocampus
MeSH
Temporal Lobe

p(HGNC:A2M) regulates a(CHEBI:"amyloid-beta") View Subject | View Object

Clearance of Aβ through the BBB is also medi- ated by α2-macroglobulin (α2M),14 and LDLR-related protein 2 (LRP2, also known as megalin) when LRP2 forms a complex with clusterin (also known as ApoJ). PubMed:26195256

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MeSH
Hippocampus
MeSH
Temporal Lobe

p(HGNC:ABCB1) increases tloc(a(CHEBI:"amyloid-beta")) View Subject | View Object

The main ABC transporter responsible for Aβ efflux is ABCB1 (also known as P-glycoprotein 1 or MDR1),which directly exports Aβ into the circulation. PubMed:26195256

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MeSH
Hippocampus
MeSH
Temporal Lobe

p(HGNC:ABCB1) increases tloc(a(CHEBI:"amyloid-beta")) View Subject | View Object

The main ABC transporter responsible for Aβ efflux is ABCB1 (also known as P-glycoprotein 1 or MDR1), which directly exports Aβ into the circulation. PubMed:26195256

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Annotations
MeSH
Hippocampus
MeSH
Temporal Lobe

p(HGNC:ACE) decreases a(CHEBI:"amyloid-beta", loc(GO:intracellular)) View Subject | View Object

Extracellular Aβ can also be degraded by proteases, such as neprily- sin (a membrane-anchored zinc metalloendopeptidase that degrades the Aβ monomers Aβ1-40 and Aβ1-42, and Aβ oligomers),119 matrix metalloproteinases 2, 3 and 9,120 glutamate carboxypeptidase II,121 endothelin-converting enzyme,122 tissue plasminogen activator,123 plasmin,120 angiotensin-converting enzyme,120 and insulin-degrading enzyme. PubMed:26195256

Appears in Networks:

p(HGNC:AGER) increases tloc(a(CHEBI:"amyloid-beta")) View Subject | View Object

Free Aβ can be transported from the circulation into the interstitium via RAGE (advanced glycosylation end product-specific receptor). PubMed:26195256

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MeSH
Hippocampus
MeSH
Temporal Lobe

p(HGNC:APOE) regulates a(CHEBI:"amyloid-beta") View Subject | View Object

which is located on the abluminal side of the brain endo- thelium,140 does not directly bind and extrude Aβ,141 but mediates Aβ clearance in an ApoE-dependent manner. PubMed:26195256

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Annotations
MeSH
Hippocampus
MeSH
Temporal Lobe

p(HGNC:APOE) decreases act(a(CHEBI:"amyloid-beta")) View Subject | View Object

ApoE is a cholesterol transporter that competes with Aβ for efflux by LRP1 from the interstitium into the circula- tion; PubMed:26195256

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MeSH
Hippocampus
MeSH
Temporal Lobe

p(HGNC:APOE) regulates a(CHEBI:"amyloid-beta") View Subject | View Object

competition for shared receptors is the primary mechanism by which ApoE mediates Aβ clearance PubMed:26195256

Appears in Networks:
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MeSH
Hippocampus
MeSH
Temporal Lobe

p(HGNC:IDE) decreases a(CHEBI:"amyloid-beta", loc(GO:intracellular)) View Subject | View Object

Extracellular Aβ can also be degraded by proteases, such as neprily- sin (a membrane-anchored zinc metalloendopeptidase that degrades the Aβ monomers Aβ1-40 and Aβ1-42, and Aβ oligomers),119 matrix metalloproteinases 2, 3 and 9,120 glutamate carboxypeptidase II,121 endothelin-converting enzyme,122 tissue plasminogen activator,123 plasmin,120 angiotensin-converting enzyme,120 and insulin-degrading enzyme. PubMed:26195256

Appears in Networks:

p(HGNC:LRP1) increases tloc(a(CHEBI:"amyloid-beta")) View Subject | View Object

Some evidence suggests that LRP1 is the main transporter for Aβ efflux at the BBB, whereas other studies have demonstrated its role to be quite minor. PubMed:26195256

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MeSH
Hippocampus
MeSH
Temporal Lobe

p(HGNC:LRP1) increases tloc(a(CHEBI:"amyloid-beta"), fromLoc(MESH:"Nephritis, Interstitial"), toLoc(MESH:Brain)) View Subject | View Object

Specifically, local soluble Aβ is transferred from the interstitium to the brain by LDL receptor (LDLR) family members such as LRP1, and ATP-binding cassette transporters (ABC transporters). PubMed:26195256

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MeSH
Hippocampus
MeSH
Temporal Lobe

p(HGNC:LRP1) increases tloc(a(CHEBI:"amyloid-beta")) View Subject | View Object

ApoE is a cholesterol transporter that competes with Aβ for efflux by LRP1 from the interstitium into the circula- tion; PubMed:26195256

Appears in Networks:
Annotations
MeSH
Hippocampus
MeSH
Temporal Lobe

p(HGNC:LRP2) regulates a(CHEBI:"amyloid-beta") View Subject | View Object

Clearance of Aβ through the BBB is also medi- ated by α2-macroglobulin (α2M),14 and LDLR-related protein 2 (LRP2, also known as megalin) when LRP2 forms a complex with clusterin (also known as ApoJ). PubMed:26195256

Appears in Networks:
Annotations
MeSH
Hippocampus
MeSH
Temporal Lobe

act(p(MESH:"Amyloid Precursor Protein Secretases")) increases a(CHEBI:"amyloid-beta") View Subject | View Object

APP is cleaved by α-secretase, which precludes forma- tion of Aβ, and the resulting carboxy-terminal fragment is then cleaved by γ-secretase.103 The resulting products do not aggregate.104 PubMed:26195256

Appears in Networks:

p(MESH:"Endothelin-Converting Enzymes") decreases a(CHEBI:"amyloid-beta", loc(GO:intracellular)) View Subject | View Object

Extracellular Aβ can also be degraded by proteases, such as neprily- sin (a membrane-anchored zinc metalloendopeptidase that degrades the Aβ monomers Aβ1-40 and Aβ1-42, and Aβ oligomers),119 matrix metalloproteinases 2, 3 and 9,120 glutamate carboxypeptidase II,121 endothelin-converting enzyme,122 tissue plasminogen activator,123 plasmin,120 angiotensin-converting enzyme,120 and insulin-degrading enzyme. PubMed:26195256

Appears in Networks:

act(p(MESH:Cathepsins)) decreases a(CHEBI:"amyloid-beta", loc(GO:intracellular)) View Subject | View Object

Intracellular Aβ (iAβ) can be degraded by proteasomes via the ubiquitin–proteasome pathway in neurons,116 lyso- somal cathepsin enzymes,117 proteases (such as insulin- degrading enzyme, a thiol metalloendopeptidase that degrades monomeric Aβ) and insulin. PubMed:26195256

Appears in Networks:

p(MESH:"Glutamate Carboxypeptidase II") decreases a(CHEBI:"amyloid-beta", loc(GO:intracellular)) View Subject | View Object

Extracellular Aβ can also be degraded by proteases, such as neprily- sin (a membrane-anchored zinc metalloendopeptidase that degrades the Aβ monomers Aβ1-40 and Aβ1-42, and Aβ oligomers),119 matrix metalloproteinases 2, 3 and 9,120 glutamate carboxypeptidase II,121 endothelin-converting enzyme,122 tissue plasminogen activator,123 plasmin,120 angiotensin-converting enzyme,120 and insulin-degrading enzyme. PubMed:26195256

Appears in Networks:

p(MESH:"Matrix Metalloproteinase 2") decreases a(CHEBI:"amyloid-beta", loc(GO:intracellular)) View Subject | View Object

Extracellular Aβ can also be degraded by proteases, such as neprily- sin (a membrane-anchored zinc metalloendopeptidase that degrades the Aβ monomers Aβ1-40 and Aβ1-42, and Aβ oligomers),119 matrix metalloproteinases 2, 3 and 9,120 glutamate carboxypeptidase II,121 endothelin-converting enzyme,122 tissue plasminogen activator,123 plasmin,120 angiotensin-converting enzyme,120 and insulin-degrading enzyme. PubMed:26195256

Appears in Networks:

p(MESH:"Matrix Metalloproteinase 3") decreases a(CHEBI:"amyloid-beta", loc(GO:intracellular)) View Subject | View Object

Extracellular Aβ can also be degraded by proteases, such as neprily- sin (a membrane-anchored zinc metalloendopeptidase that degrades the Aβ monomers Aβ1-40 and Aβ1-42, and Aβ oligomers),119 matrix metalloproteinases 2, 3 and 9,120 glutamate carboxypeptidase II,121 endothelin-converting enzyme,122 tissue plasminogen activator,123 plasmin,120 angiotensin-converting enzyme,120 and insulin-degrading enzyme. PubMed:26195256

Appears in Networks:

p(MESH:"Matrix Metalloproteinase 9") decreases a(CHEBI:"amyloid-beta", loc(GO:intracellular)) View Subject | View Object

Extracellular Aβ can also be degraded by proteases, such as neprily- sin (a membrane-anchored zinc metalloendopeptidase that degrades the Aβ monomers Aβ1-40 and Aβ1-42, and Aβ oligomers),119 matrix metalloproteinases 2, 3 and 9,120 glutamate carboxypeptidase II,121 endothelin-converting enzyme,122 tissue plasminogen activator,123 plasmin,120 angiotensin-converting enzyme,120 and insulin-degrading enzyme. PubMed:26195256

Appears in Networks:

p(MESH:"Tissue Plasminogen Activator") decreases a(CHEBI:"amyloid-beta", loc(GO:intracellular)) View Subject | View Object

Extracellular Aβ can also be degraded by proteases, such as neprily- sin (a membrane-anchored zinc metalloendopeptidase that degrades the Aβ monomers Aβ1-40 and Aβ1-42, and Aβ oligomers),119 matrix metalloproteinases 2, 3 and 9,120 glutamate carboxypeptidase II,121 endothelin-converting enzyme,122 tissue plasminogen activator,123 plasmin,120 angiotensin-converting enzyme,120 and insulin-degrading enzyme. PubMed:26195256

Appears in Networks:

p(MESH:Fibrinolysin) decreases a(CHEBI:"amyloid-beta", loc(GO:intracellular)) View Subject | View Object

Extracellular Aβ can also be degraded by proteases, such as neprily- sin (a membrane-anchored zinc metalloendopeptidase that degrades the Aβ monomers Aβ1-40 and Aβ1-42, and Aβ oligomers),119 matrix metalloproteinases 2, 3 and 9,120 glutamate carboxypeptidase II,121 endothelin-converting enzyme,122 tissue plasminogen activator,123 plasmin,120 angiotensin-converting enzyme,120 and insulin-degrading enzyme. PubMed:26195256

Appears in Networks:

p(MESH:Neprilysin) decreases a(CHEBI:"amyloid-beta", loc(GO:intracellular)) View Subject | View Object

Extracellular Aβ can also be degraded by proteases, such as neprily- sin (a membrane-anchored zinc metalloendopeptidase that degrades the Aβ monomers Aβ1-40 and Aβ1-42, and Aβ oligomers),119 matrix metalloproteinases 2, 3 and 9,120 glutamate carboxypeptidase II,121 endothelin-converting enzyme,122 tissue plasminogen activator,123 plasmin,120 angiotensin-converting enzyme,120 and insulin-degrading enzyme. PubMed:26195256

Appears in Networks:

act(p(MESH:Ubiquitin)) decreases a(CHEBI:"amyloid-beta", loc(GO:intracellular)) View Subject | View Object

Intracellular Aβ (iAβ) can be degraded by proteasomes via the ubiquitin–proteasome pathway in neurons,116 lyso- somal cathepsin enzymes,117 proteases (such as insulin- degrading enzyme, a thiol metalloendopeptidase that degrades monomeric Aβ) and insulin. PubMed:26195256

Appears in Networks:

act(p(MGI:Aqp4)) decreases a(CHEBI:"amyloid-beta") View Subject | View Object

Recent mouse studies suggest that the AQP4-dependent glymphatic pathway is an important clearance system for driving the removal of soluble Aβ from the interstitium. PubMed:26195256

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MeSH
Hippocampus
MeSH
Temporal Lobe

path(HBP:"high-fat prenatal maternal diet") increases a(CHEBI:"amyloid-beta") View Subject | View Object

Of note, a high-fat prenatal maternal diet has recently been reported to result in a failure of Aβ clearance along cerebrovascular basement membranes. PubMed:26195256

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MeSH
Hippocampus
MeSH
Temporal Lobe

a(CHEBI:"alpha,alpha-trehalose") decreases a(CHEBI:"amyloid-beta") View Subject | View Object

Trehalose also can reduce Aβ levels in hippocampus (Du et al. 2013) PubMed:29626319

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MeSH
Hippocampus

tloc(a(CHEBI:"amyloid-beta"), fromLoc(MESH:Brain), toLoc(MESH:Blood)) decreases a(CHEBI:"amyloid-beta") View Subject | View Object

By collecting time-matched blood samples from cerebral vein, femoral vein, and radial artery in patients to measure the concentration of Aβ for every blood sample and figure out the turnover of it from vein to artery, it has been shown that transport of Aβ from brain to blood via the BBB and CSF absorption accounts for half of the total clearance of Aβ in CNS in humans, and furthermore, the clearance rate of Aβ via the BBB and CSF absorption accounts for the same proportion (Roberts et al. 2014) PubMed:29626319

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a(CHEBI:"disodium cromoglycate") decreases a(CHEBI:"amyloid-beta") View Subject | View Object

It has been discovered that cromolyn sodium, already used in the cure for asthma, can enter the central nervous system and promote Aβ monomer clearance by microglial phagocytosis (Hori et al. 2015) PubMed:29626319

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a(CHEBI:"docosahexaenoic acid") increases deg(a(CHEBI:"amyloid-beta")) View Subject | View Object

Dietary pre-administration of docosahexaenoic acid prevents RBCs from oxidative damage due to its antioxidative characteristic and also increases Aβ degradation by RBC in a lipid raft-dependent manner (Hashimoto et al. 2015) PubMed:29626319

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a(CHEBI:"omega-3 fatty acid") increases deg(a(CHEBI:"amyloid-beta")) View Subject | View Object

A recent study showed that omega-3 polyunsaturated fatty acids also increase Aβ degradation by proteases PubMed:29626319

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a(CHEBI:Temsirolimus) decreases a(CHEBI:"amyloid-beta") View Subject | View Object

Wogonin, rapamycin, and temsirolimus have been considered to improve the activity of autophagy to increase Aβ clearance and inhibit tau phosphorylation via targeting mTOR signaling (Caccamo et al. 2010; Jiang et al. 2014c; Jiang et al. 2014d; Spilman et al. 2010; Zhu andWang 2015) PubMed:29626319

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a(CHEBI:atorvastatin) increases deg(a(CHEBI:"amyloid-beta")) View Subject | View Object

Simvastatin and atorvastatin enhance extracellular Aβ degradation via increasing NEP secretion from astrocytes by activating MAPK/Erk1/2 (Yamamoto et al. 2016) PubMed:29626319

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a(CHEBI:donepezil) decreases a(CHEBI:"amyloid-beta") View Subject | View Object

Cholinesterase inhibitors donepezil and rivastigmine, upregulating transport proteins P-glycoprotein and LRP1, may improve Aβ clearance in the liver of rats (Mohamed et al. 2015) PubMed:29626319

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a(CHEBI:minocycline) increases deg(a(CHEBI:"amyloid-beta")) View Subject | View Object

Minocycline not only suppresses pro-inflammatory phenotypes of microglia but also promotes their phagocytic clearance of Aβ (El-Shimy et al.2015) PubMed:29626319

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a(CHEBI:nobiletin) increases deg(a(CHEBI:"amyloid-beta")) View Subject | View Object

Nobiletin, a flavone from citrus depressa, leads to gene expression and improves the protein level and activity of NEP in SK-N-SH cells, thus reducing Aβ levels (Fujiwara et al. 2014) PubMed:29626319

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a(CHEBI:oleocanthal) decreases a(CHEBI:"amyloid-beta") View Subject | View Object

Oleocanthal, a special component of extra-virgin olive oil, increases cerebral clearance of Aβ across the BBB by enhancing the expression of important efflux transport proteins at the BBB containing LRP1 and P-gp, and activating the APOE-dependent Aβ clearance pathway in mice brains (Qosa et al. 2015) PubMed:29626319

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a(CHEBI:pioglitazone) decreases a(CHEBI:"amyloid-beta") View Subject | View Object

Moreover, pioglitazone seems to be an effective therapeutic approach targeting Aβ clearance via similar mechanisms to those of rosiglitazone (Mandrekar-Colucci et al. 2012) PubMed:29626319

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a(CHEBI:rivastigmine) decreases a(CHEBI:"amyloid-beta") View Subject | View Object

Cholinesterase inhibitors donepezil and rivastigmine, upregulating transport proteins P-glycoprotein and LRP1, may improve Aβ clearance in the liver of rats (Mohamed et al. 2015) PubMed:29626319

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a(CHEBI:rosiglitazone) increases deg(a(CHEBI:"amyloid-beta")) View Subject | View Object

Rosiglitazone, a highaffinity agonist for PPARγ, can clear Aβ by activating microglia and promoting its phagocytosis via increasing the levels of CD36, a receptor expressed in it (Escribano et al. 2010) PubMed:29626319

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a(CHEBI:simvastatin) increases deg(a(CHEBI:"amyloid-beta")) View Subject | View Object

Simvastatin and atorvastatin enhance extracellular Aβ degradation via increasing NEP secretion from astrocytes by activating MAPK/Erk1/2 (Yamamoto et al. 2016) PubMed:29626319

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a(CHEBI:sirolimus) decreases a(CHEBI:"amyloid-beta") View Subject | View Object

Wogonin, rapamycin, and temsirolimus have been considered to improve the activity of autophagy to increase Aβ clearance and inhibit tau phosphorylation via targeting mTOR signaling (Caccamo et al. 2010; Jiang et al. 2014c; Jiang et al. 2014d; Spilman et al. 2010; Zhu andWang 2015) PubMed:29626319

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a(CHEBI:somatostatin) increases deg(a(CHEBI:"amyloid-beta")) View Subject | View Object

Somatotatin also up-regulates the expression and secretion of IDE in order to enhance Aβ clearance (Tundo et al.2012) PubMed:29626319

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a(CHEBI:statin) increases deg(a(CHEBI:"amyloid-beta")) View Subject | View Object

Statin can lead to extracellular IDE secretion from astrocytes in an autophagy-based unconventional secretory pathway (Glebov and Walter 2012), thus enhancing the extracellular removal of Aβ PubMed:29626319

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Cell Ontology (CL)
astrocyte

tloc(a(CHEBI:water), fromLoc(GO:"extracellular region"), toLoc(MESH:"Cerebrospinal Fluid")) decreases a(CHEBI:"amyloid-beta") View Subject | View Object

In a similar manner, a recent experiment indicated that water influx into the CSF is significantly reduced in AD-patients, which may impair Aβ clearance (Suzuki et al. 2015) PubMed:29626319

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a(CHEBI:wogonin) decreases a(CHEBI:"amyloid-beta") View Subject | View Object

Wogonin, rapamycin, and temsirolimus have been considered to improve the activity of autophagy to increase Aβ clearance and inhibit tau phosphorylation via targeting mTOR signaling (Caccamo et al. 2010; Jiang et al. 2014c; Jiang et al. 2014d; Spilman et al. 2010; Zhu andWang 2015) PubMed:29626319

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a(HBP:"APOE e4") decreases deg(a(CHEBI:"amyloid-beta")) View Subject | View Object

Recent evidence has indicated that autophagy is damaged in astrocytes accompanied by the expression of APOE4, which attenuates Aβ degradation (Simonovitch et al. 2016) PubMed:29626319

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a(HBP:"APOE e4") decreases deg(a(CHEBI:"amyloid-beta")) View Subject | View Object

The expression of APOE ε4 allele is related to the reduction of Aβ clearance from the brain by impairing its arterial perivascular drainage, accompanied by changes of protein levels in cerebrovascular basement membrane (Hawkes et al. 2012) PubMed:29626319

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a(HP:"blood-cerebrospinal fluid barrier") decreases a(CHEBI:"amyloid-beta") View Subject | View Object

There is a study showing that the BCSFB is the primary removal channel compared with arachnoid villi, resulting from the receptor LRP1 expressed in epithelial cells of choroid plexus in the BCSFB (Fujiyoshi et al. 2011) PubMed:29626319

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a(HP:"glymphatic system") decreases a(CHEBI:"amyloid-beta") View Subject | View Object

In the meanwhile, a study supported this idea that AQP4 deficiency can reduce the rate of Aβ clearance via glymphatic pathway (Iliff and Nedergaard 2013) PubMed:29626319

Appears in Networks:

a(MESH:"Gastrointestinal Tract") decreases a(CHEBI:"amyloid-beta") View Subject | View Object

By measuring Aβ levels in superior vena cava and inferior vena cava, it is clear thatAβ levels are getting lower and lower along the direction of the vein blood flow, and the contents of Aβ40 and total Aβ in artery are significantly less than those in vein, suggesting a part of Aβ40 and total Aβ can be cleared by peripheral organs and tissues, such as the liver, kidney, skin, and the gastrointestinal tract, although there is no change in Aβ42 concentrations (Xiang et al. 2015) PubMed:29626319

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MeSH
Arteries

a(MESH:"Lymph Nodes") decreases a(CHEBI:"amyloid-beta") View Subject | View Object

A study suggested that Aβ is removed from CSF to cervical lymph nodes via perineural space of the olfactory nerve (Picken 2001; Pollay 2010) PubMed:29626319

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MeSH
Neck

a(MESH:"Receptors, G-Protein-Coupled") increases deg(a(CHEBI:"amyloid-beta")) View Subject | View Object

Aβ is cleared by receptor-mediated microglial phagocytosis and degradation, such as scavenger receptors, chemokine-like receptor 1, toll-like receptors, and G protein-coupled receptors including formyl peptide receptor 2 (Yu and Ye 2015) PubMed:29626319

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a(MESH:"Receptors, Scavenger") increases deg(a(CHEBI:"amyloid-beta")) View Subject | View Object

Aβ is cleared by receptor-mediated microglial phagocytosis and degradation, such as scavenger receptors, chemokine-like receptor 1, toll-like receptors, and G protein-coupled receptors including formyl peptide receptor 2 (Yu and Ye 2015) PubMed:29626319

Appears in Networks:

a(MESH:Erythrocytes) increases deg(a(CHEBI:"amyloid-beta")) View Subject | View Object

Aβ in periphery is mainly cleared by blood components, such as red cells (RBCs) and monocytes, or some tissues and organs, such as the liver and kidney (Fig. 2) PubMed:29626319

Appears in Networks:

a(MESH:Erythrocytes) increases deg(a(CHEBI:"amyloid-beta")) View Subject | View Object

Dietary pre-administration of docosahexaenoic acid prevents RBCs from oxidative damage due to its antioxidative characteristic and also increases Aβ degradation by RBC in a lipid raft-dependent manner (Hashimoto et al. 2015) PubMed:29626319

Appears in Networks:

a(MESH:Kidney) increases deg(a(CHEBI:"amyloid-beta")) View Subject | View Object

Aβ in periphery is mainly cleared by blood components, such as red cells (RBCs) and monocytes, or some tissues and organs, such as the liver and kidney (Fig. 2) PubMed:29626319

Appears in Networks:

a(MESH:Kidney) decreases a(CHEBI:"amyloid-beta") View Subject | View Object

By measuring Aβ levels in superior vena cava and inferior vena cava, it is clear thatAβ levels are getting lower and lower along the direction of the vein blood flow, and the contents of Aβ40 and total Aβ in artery are significantly less than those in vein, suggesting a part of Aβ40 and total Aβ can be cleared by peripheral organs and tissues, such as the liver, kidney, skin, and the gastrointestinal tract, although there is no change in Aβ42 concentrations (Xiang et al. 2015) PubMed:29626319

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MeSH
Arteries

a(MESH:Kidney) decreases a(CHEBI:"amyloid-beta") View Subject | View Object

Among these peripheral organs and tissues mentioned above, the liver and kidney are considered to be the major organs for the clearance of Aβ in periphery (Ghiso et al. 2004) PubMed:29626319

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a(MESH:Liver) increases deg(a(CHEBI:"amyloid-beta")) View Subject | View Object

Aβ in periphery is mainly cleared by blood components, such as red cells (RBCs) and monocytes, or some tissues and organs, such as the liver and kidney (Fig. 2) PubMed:29626319

Appears in Networks:

a(MESH:Liver) decreases a(CHEBI:"amyloid-beta") View Subject | View Object

By measuring Aβ levels in superior vena cava and inferior vena cava, it is clear thatAβ levels are getting lower and lower along the direction of the vein blood flow, and the contents of Aβ40 and total Aβ in artery are significantly less than those in vein, suggesting a part of Aβ40 and total Aβ can be cleared by peripheral organs and tissues, such as the liver, kidney, skin, and the gastrointestinal tract, although there is no change in Aβ42 concentrations (Xiang et al. 2015) PubMed:29626319

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MeSH
Arteries

a(MESH:Liver) decreases a(CHEBI:"amyloid-beta") View Subject | View Object

Among these peripheral organs and tissues mentioned above, the liver and kidney are considered to be the major organs for the clearance of Aβ in periphery (Ghiso et al. 2004) PubMed:29626319

Appears in Networks:

a(MESH:Monocytes) increases deg(a(CHEBI:"amyloid-beta")) View Subject | View Object

Aβ in periphery is mainly cleared by blood components, such as red cells (RBCs) and monocytes, or some tissues and organs, such as the liver and kidney (Fig. 2) PubMed:29626319

Appears in Networks:

a(MESH:Monocytes) increases deg(a(CHEBI:"amyloid-beta")) View Subject | View Object

Monocytes in peripheral blood have been demonstrated to play an important role in clearing Aβ that diffuses from brain to blood (Halle et al. 2015) PubMed:29626319

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a(MESH:Skin) decreases a(CHEBI:"amyloid-beta") View Subject | View Object

By measuring Aβ levels in superior vena cava and inferior vena cava, it is clear thatAβ levels are getting lower and lower along the direction of the vein blood flow, and the contents of Aβ40 and total Aβ in artery are significantly less than those in vein, suggesting a part of Aβ40 and total Aβ can be cleared by peripheral organs and tissues, such as the liver, kidney, skin, and the gastrointestinal tract, although there is no change in Aβ42 concentrations (Xiang et al. 2015) PubMed:29626319

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MeSH
Arteries

bp(GO:"lysosomal microautophagy") increases deg(a(CHEBI:"amyloid-beta")) View Subject | View Object

Intracellular Aβ clearance can be achieved through UPS and ALS, and extracellular Aβ is degraded by glial phagocytosis, such as microglia, astrocytes, and proteases from neurons and astrocytes (Fig. 2) PubMed:29626319

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MeSH
Intracellular Space

bp(GO:"lysosomal microautophagy") increases deg(a(CHEBI:"amyloid-beta")) View Subject | View Object

Intracellular Aβ degradation pathways mainly contain two major pathways: UPS and ALS (Vilchez et al. 2014) PubMed:29626319

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MeSH
Intracellular Space

bp(GO:"lysosomal microautophagy") increases deg(a(CHEBI:"amyloid-beta")) View Subject | View Object

In addition, there is accumulating evidence to prove that Aβ can be cleared by ALS. PubMed:29626319

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bp(GO:"proteasome-mediated ubiquitin-dependent protein catabolic process") increases deg(a(CHEBI:"amyloid-beta")) View Subject | View Object

Intracellular Aβ clearance can be achieved through UPS and ALS, and extracellular Aβ is degraded by glial phagocytosis, such as microglia, astrocytes, and proteases from neurons and astrocytes (Fig. 2) PubMed:29626319

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MeSH
Intracellular Space

bp(GO:"proteasome-mediated ubiquitin-dependent protein catabolic process") increases deg(a(CHEBI:"amyloid-beta")) View Subject | View Object

Intracellular Aβ degradation pathways mainly contain two major pathways: UPS and ALS (Vilchez et al. 2014) PubMed:29626319

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MeSH
Intracellular Space

bp(GO:aging) positiveCorrelation a(CHEBI:"amyloid-beta") View Subject | View Object

Meanwhile, an animal experiment showed that IDE expression will descend with age and diabetes, then resulting in Aβ deposition (Kochkina et al. 2015) PubMed:29626319

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bp(GO:phagocytosis) increases deg(a(CHEBI:"amyloid-beta")) View Subject | View Object

Intracellular Aβ clearance can be achieved through UPS and ALS, and extracellular Aβ is degraded by glial phagocytosis, such as microglia, astrocytes, and proteases from neurons and astrocytes (Fig. 2) PubMed:29626319

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MeSH
Extracellular Space

bp(GO:phagocytosis) increases deg(a(CHEBI:"amyloid-beta")) View Subject | View Object

Microglial cells, the key immune cells of the brain, play an important part in the phagocytosis of Aβ PubMed:29626319

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bp(GO:phagocytosis) increases deg(a(CHEBI:"amyloid-beta")) View Subject | View Object

Aβ is cleared by receptor-mediated microglial phagocytosis and degradation, such as scavenger receptors, chemokine-like receptor 1, toll-like receptors, and G protein-coupled receptors including formyl peptide receptor 2 (Yu and Ye 2015) PubMed:29626319

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bp(GO:proteolysis) increases deg(a(CHEBI:"amyloid-beta")) View Subject | View Object

The proteolytic degradation is also a major pathway of Aβ clearance PubMed:29626319

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complex(FPLX:"Gamma_secretase") increases a(CHEBI:"amyloid-beta") View Subject | View Object

Under normal conditions, Aβ production in brain parenchyma results from hydrolyzing amyloid precursor proteins via beta-secreted enzymes and gamma-secreted enzymes, and the most common subtypes of Aβ in human body are Aβ1–40 and Aβ1–42 PubMed:29626319

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complex(a(CHEBI:"amyloid-beta"), p(HGNC:TTR)) hasComponent a(CHEBI:"amyloid-beta") View Subject | View Object

Appears in Networks:

complex(a(CHEBI:"amyloid-beta"), p(HGNC:TTR)) increases deg(a(CHEBI:"amyloid-beta")) View Subject | View Object

Moreover, researchers reported that TTR, a transporter protein mainly synthesized in the CP of the brain and secreted into the CSF, can reduce the Aβ contents in brain (Ribeiro et al. 2014), which gives us inspiration that TTR bound to Aβ may be a natural mechanism of brain Aβ clearance PubMed:29626319

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MeSH
Brain
MeSH
Cerebrospinal Fluid

complex(a(MESH:"Chemokine CX3CL1"), p(HGNC:CX3CR1)) increases deg(a(CHEBI:"amyloid-beta")) View Subject | View Object

Fractalkine can keep microglia in the right state via interacting with CX3CR, thus contributing to Aβ clearance PubMed:29626319

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complex(a(MESH:Erythrocytes), p(HGNC:CR1)) increases deg(a(CHEBI:"amyloid-beta")) View Subject | View Object

It is known that RBCs can facilitate Aβ clearance relying on complement C3b-dependent adherence to complement receptor 1(CR1) on RBCs (Rogers et al. 2006) PubMed:29626319

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composite(a(CHEBI:"amyloid-beta"), a(MESH:"Serum Albumin")) hasComponent a(CHEBI:"amyloid-beta") View Subject | View Object

Appears in Networks:

composite(a(CHEBI:"amyloid-beta"), a(MESH:"Serum Albumin")) decreases a(CHEBI:"amyloid-beta") View Subject | View Object

In addition, a recent experiment showed that a great deal of Aβ in the blood circulation may combine with serum albumin (Stanyon and Viles 2012), which provided a novel clearance pathway in periphery PubMed:29626319

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p(FPLX:HSPA) increases deg(a(CHEBI:"amyloid-beta")) View Subject | View Object

Exercise training can increase extracellular Aβ clearance in the brains of Tg2576 mice in a dose-dependent manner through up-regulating NEP, IDE, MMP9, LRP1, and HSP70 (Moore et al. 2016) PubMed:29626319

Appears in Networks:

p(FPLX:MMP) increases deg(a(CHEBI:"amyloid-beta")) View Subject | View Object

Extracellular Aβ degrading enzymes include neprilysin (NEP), insulin-degrading enzyme (IDE), matrix metalloproteinases (MMPs), angiotensin converting enzyme (ACE), endothelin-converting enzyme (ECE), and plasmin (Baranello et al. 2015) PubMed:29626319

Appears in Networks:

p(FPLX:TLR) increases deg(a(CHEBI:"amyloid-beta")) View Subject | View Object

Aβ is cleared by receptor-mediated microglial phagocytosis and degradation, such as scavenger receptors, chemokine-like receptor 1, toll-like receptors, and G protein-coupled receptors including formyl peptide receptor 2 (Yu and Ye 2015) PubMed:29626319

Appears in Networks:

p(HGNC:ABCA7) decreases a(CHEBI:"amyloid-beta") View Subject | View Object

A recent study has shown that ABCA7, mainly expressed in human microglial cells, also regulates microglial phagocytic function and decreases Aβ deposition (Zhao et al. 2015a) PubMed:29626319

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Cell Ontology (CL)
microglial cell

p(HGNC:ABCA7) decreases a(CHEBI:"amyloid-beta") View Subject | View Object

However, current evidence showed that ATP-binding cassette transporter A7 deficit can increase Aβ deposition in brain by promoting Aβ-production through increasing β-secretase 1 levels rather than influencing the clearance of Aβ in APP/PS1 mice (Sakae et al. 2016) PubMed:29626319

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p(HGNC:ABCB1) increases tloc(a(CHEBI:"amyloid-beta"), fromLoc(MESH:Brain), toLoc(GO:"extracellular region")) View Subject | View Object

And meanwhile, P-glycoprotein (Pgp), as an efflux transporter, highly expressed on the lumen surface of the BBB, has been proven to transport Aβ out of brain (van Assema et al. 2012; Wei et al. 2016) PubMed:29626319

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p(HGNC:ABCB1) decreases a(CHEBI:"amyloid-beta") View Subject | View Object

However, recently, it has been reported that the expression and transport activity of P-gp are impaired in sporadic AD as a result of its ubiquitination, internalization, and proteasome-dependent degradation derived from Aβ40 (Chiu et al. 2015; Hartz et al. 2016), which will result in Aβ deposition PubMed:29626319

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p(HGNC:ACE) increases deg(a(CHEBI:"amyloid-beta")) View Subject | View Object

Extracellular Aβ degrading enzymes include neprilysin (NEP), insulin-degrading enzyme (IDE), matrix metalloproteinases (MMPs), angiotensin converting enzyme (ACE), endothelin-converting enzyme (ECE), and plasmin (Baranello et al. 2015) PubMed:29626319

Appears in Networks:

p(HGNC:ACE) increases deg(a(CHEBI:"amyloid-beta")) 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

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p(HGNC:CD33) decreases deg(a(CHEBI:"amyloid-beta")) View Subject | View Object

Besides, CD33, most abundantly expressed in microglia in AD, inhibits normal function of immune cells and impairs microglia-mediated clearance of Aβ (Jiang et al. 2014b) PubMed:29626319

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p(HGNC:AGER) increases tloc(a(CHEBI:"amyloid-beta"), fromLoc(GO:"extracellular region"), toLoc(GO:intracellular)) View Subject | View Object

In addition, the luminal residing receptor for advanced glycation end products (RAGE) is an Aβ influx transporter (Deane et al. 2003) PubMed:29626319

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p(HGNC:ANXA1) increases deg(a(CHEBI:"amyloid-beta")) View Subject | View Object

Anti-inflammatory mediator annexin A1 (ANXA1) can reduce Aβ content by increasing its degradation by NEP (Ries et al. 2016) PubMed:29626319

Appears in Networks:

p(HGNC:AQP1) decreases a(CHEBI:"amyloid-beta") View Subject | View Object

It has been shown that choroid plexus dysfunction, due to the reductive expression of epithelial aquaporin-1, a water channel protein, can induce CSF production, which in turn damages Aβ clearance in a triple transgenic mouse model of AD (Gonzalez-Marrero et al. 2015) PubMed:29626319

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p(HGNC:AQP4) association deg(a(CHEBI:"amyloid-beta")) View Subject | View Object

In addition, Jeffrey J. Iliff et al. have demonstrated that the Aβ in brain interstitium can be eliminated from the parenchyma by the bulk flow of interstitial fluid, which also depends on a water channel aquaporin-4 (AQP4) expressed in astrocyte endfeet PubMed:29626319

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p(HGNC:AQP4) decreases a(CHEBI:"amyloid-beta") View Subject | View Object

Consistent with the conclusion above, there is evidence that glymphatic drainage of ISF bulk flow relying on water channel AQP4 can decrease the levels of Aβ in brain (Iliff et al. 2012) PubMed:29626319

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MeSH
Brain

p(HGNC:AQP4) decreases a(CHEBI:"amyloid-beta") View Subject | View Object

In the meanwhile, a study supported this idea that AQP4 deficiency can reduce the rate of Aβ clearance via glymphatic pathway (Iliff and Nedergaard 2013) PubMed:29626319

Appears in Networks:

p(HGNC:BACE1) increases a(CHEBI:"amyloid-beta") View Subject | View Object

Under normal conditions, Aβ production in brain parenchyma results from hydrolyzing amyloid precursor proteins via beta-secreted enzymes and gamma-secreted enzymes, and the most common subtypes of Aβ in human body are Aβ1–40 and Aβ1–42 PubMed:29626319

Appears in Networks:

p(HGNC:CMKLR1) increases deg(a(CHEBI:"amyloid-beta")) View Subject | View Object

Aβ is cleared by receptor-mediated microglial phagocytosis and degradation, such as scavenger receptors, chemokine-like receptor 1, toll-like receptors, and G protein-coupled receptors including formyl peptide receptor 2 (Yu and Ye 2015) PubMed:29626319

Appears in Networks:

p(HGNC:ECE1) increases deg(a(CHEBI:"amyloid-beta")) View Subject | View Object

Extracellular Aβ degrading enzymes include neprilysin (NEP), insulin-degrading enzyme (IDE), matrix metalloproteinases (MMPs), angiotensin converting enzyme (ACE), endothelin-converting enzyme (ECE), and plasmin (Baranello et al. 2015) PubMed:29626319

Appears in Networks:

p(HGNC:FPR2) increases deg(a(CHEBI:"amyloid-beta")) View Subject | View Object

Aβ is cleared by receptor-mediated microglial phagocytosis and degradation, such as scavenger receptors, chemokine-like receptor 1, toll-like receptors, and G protein-coupled receptors including formyl peptide receptor 2 (Yu and Ye 2015) PubMed:29626319

Appears in Networks:

p(HGNC:IDE) increases deg(a(CHEBI:"amyloid-beta")) View Subject | View Object

Extracellular Aβ degrading enzymes include neprilysin (NEP), insulin-degrading enzyme (IDE), matrix metalloproteinases (MMPs), angiotensin converting enzyme (ACE), endothelin-converting enzyme (ECE), and plasmin (Baranello et al. 2015) PubMed:29626319

Appears in Networks:

p(HGNC:IDE) increases deg(a(CHEBI:"amyloid-beta")) View Subject | View Object

IDE, a zinc endopeptidase, can degrade extracellular Aβ (Vekrellis et al. 2000) PubMed:29626319

Appears in Networks:

p(HGNC:IDE) increases deg(a(CHEBI:"amyloid-beta")) View Subject | View Object

Exercise training can increase extracellular Aβ clearance in the brains of Tg2576 mice in a dose-dependent manner through up-regulating NEP, IDE, MMP9, LRP1, and HSP70 (Moore et al. 2016) PubMed:29626319

Appears in Networks:

p(HGNC:LRP1) increases tloc(a(CHEBI:"amyloid-beta"), fromLoc(MESH:Brain), toLoc(MESH:Blood)) View Subject | View Object

LRP1, efflux transporter protein, is expressed mainly at the abluminal membrane of the BBB and highly expressive LRP1 can elevate the rate of Aβ clearance from brain to blood (Pflanzner et al. 2011) PubMed:29626319

Appears in Networks:

p(HGNC:LRP1) increases deg(a(CHEBI:"amyloid-beta")) View Subject | View Object

GLUT1, glucose transporter expressed in the BBB, regulates LRP1-dependent Aβ clearance via increasing the expression of LRP1 PubMed:29626319

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MeSH
Blood-Brain Barrier

p(HGNC:LRP1) increases deg(a(CHEBI:"amyloid-beta")) View Subject | View Object

Exercise training can increase extracellular Aβ clearance in the brains of Tg2576 mice in a dose-dependent manner through up-regulating NEP, IDE, MMP9, LRP1, and HSP70 (Moore et al. 2016) PubMed:29626319

Appears in Networks:

p(HGNC:MME) increases deg(a(CHEBI:"amyloid-beta")) View Subject | View Object

Extracellular Aβ degrading enzymes include neprilysin (NEP), insulin-degrading enzyme (IDE), matrix metalloproteinases (MMPs), angiotensin converting enzyme (ACE), endothelin-converting enzyme (ECE), and plasmin (Baranello et al. 2015) PubMed:29626319

Appears in Networks:

p(HGNC:MME) increases deg(a(CHEBI:"amyloid-beta")) View Subject | View Object

NEP, plasma membrane glycoprotein, is a zinc metalloendopeptidase and the most efficient hydrolytic enzyme in degrading Aβ in vitro (Shirotani et al. 2001) PubMed:29626319

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p(HGNC:MME) increases deg(a(CHEBI:"amyloid-beta")) View Subject | View Object

And in APP transgenic mice, long-term gene therapy of NEP ameliorates behavior by lowering the levels of Aβ (Spencer et al. 2008) PubMed:29626319

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p(HGNC:MME) increases deg(a(CHEBI:"amyloid-beta")) View Subject | View Object

Exercise training can increase extracellular Aβ clearance in the brains of Tg2576 mice in a dose-dependent manner through up-regulating NEP, IDE, MMP9, LRP1, and HSP70 (Moore et al. 2016) PubMed:29626319

Appears in Networks:

act(p(HGNC:MME)) increases deg(a(CHEBI:"amyloid-beta")) View Subject | View Object

Anti-inflammatory mediator annexin A1 (ANXA1) can reduce Aβ content by increasing its degradation by NEP (Ries et al. 2016) PubMed:29626319

Appears in Networks:

act(p(HGNC:MMP2)) increases deg(a(CHEBI:"amyloid-beta")) View Subject | View Object

Among MMPs, MMP-2, -3 and -9, stimulated by Aβ, play important roles in degrading Aβ (Wang et al. 2014) PubMed:29626319

Appears in Networks:

act(p(HGNC:MMP3)) increases deg(a(CHEBI:"amyloid-beta")) View Subject | View Object

Among MMPs, MMP-2, -3 and -9, stimulated by Aβ, play important roles in degrading Aβ (Wang et al. 2014) PubMed:29626319

Appears in Networks:

act(p(HGNC:MMP9)) increases deg(a(CHEBI:"amyloid-beta")) View Subject | View Object

Among MMPs, MMP-2, -3 and -9, stimulated by Aβ, play important roles in degrading Aβ (Wang et al. 2014) PubMed:29626319

Appears in Networks:

p(HGNC:MMP9) increases deg(a(CHEBI:"amyloid-beta")) View Subject | View Object

Exercise training can increase extracellular Aβ clearance in the brains of Tg2576 mice in a dose-dependent manner through up-regulating NEP, IDE, MMP9, LRP1, and HSP70 (Moore et al. 2016) PubMed:29626319

Appears in Networks:

p(HGNC:PICALM) increases tloc(a(CHEBI:"amyloid-beta"), fromLoc(MESH:"Blood-Brain Barrier"), toLoc(MESH:Blood)) View Subject | View Object

PICALM, mainly expressed in endothelial cells of vascular walls, contributes to the transport of Aβ across the BBB into blood (Xu et al. 2015) PubMed:29626319

Appears in Networks:

p(HGNC:PICALM) decreases a(CHEBI:"amyloid-beta") View Subject | View Object

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

Appears in Networks:
Annotations
MeSH
Alzheimer Disease

p(HGNC:SERPINF2) increases deg(a(CHEBI:"amyloid-beta")) View Subject | View Object

Extracellular Aβ degrading enzymes include neprilysin (NEP), insulin-degrading enzyme (IDE), matrix metalloproteinases (MMPs), angiotensin converting enzyme (ACE), endothelin-converting enzyme (ECE), and plasmin (Baranello et al. 2015) PubMed:29626319

Appears in Networks:

p(HGNC:SERPINF2) increases deg(a(CHEBI:"amyloid-beta")) View Subject | View Object

Brain plasmin degrades Aβ PubMed:29626319

Appears in Networks:

p(HGNC:SLC2A1) regulates deg(a(CHEBI:"amyloid-beta")) View Subject | View Object

GLUT1, glucose transporter expressed in the BBB, regulates LRP1-dependent Aβ clearance via increasing the expression of LRP1 PubMed:29626319

Appears in Networks:
Annotations
MeSH
Blood-Brain Barrier

p(HGNC:SLC2A1) regulates tloc(a(CHEBI:"amyloid-beta"), fromLoc(MESH:Brain), toLoc(MESH:Blood)) View Subject | View Object

In addition, the transport of GLUT1-mediated glucose into the brain is also beneficial to maintaining the integrity of the BBB, thereby ensuring the normal transport of Aβ from brain into blood (Winkler et al. 2015) PubMed:29626319

Appears in Networks:

p(HGNC:TFEB) decreases a(CHEBI:"amyloid-beta") View Subject | View Object

Transcriptional factor EB downregulates Aβ levels by affecting autophagy-lysosome (Zhang and Zhao 2015) PubMed:29626319

Appears in Networks:

p(HGNC:TFEB) increases deg(a(CHEBI:"amyloid-beta")) View Subject | View Object

Xiao et al. have also obtained the consistent conclusion that transcriptional factor EB, a master regulator of lysosome biogenesis, improves lysosomal function in astrocytes, which may promote Aβ clearance and attenuate plaque pathogenesis (Xiao et al. 2014) PubMed:29626319

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Annotations
MeSH
Astrocytes

p(HGNC:TFEB) regulates deg(a(CHEBI:"amyloid-beta")) View Subject | View Object

For example, like Aβ, clearance of pTau/NFT also can be regulated by TFEB, which increases the activity of autophagy and lysosome (Polito et al. 2014) PubMed:29626319

Appears in Networks:

p(HGNC:TREM2, var("p.Arg47His")) increases a(CHEBI:"amyloid-beta") View Subject | View Object

However, due to the presence of the R47H mutation in AD, TREM2 cannot effectively recognize the lipid ligands and then fails to activate microglia, which leads to Aβ deposition (Jiang et al. 2014a; Jiang et al. 2013) PubMed:29626319

Appears in Networks:
Annotations
MeSH
Alzheimer Disease

p(HGNC:UBB, var("?")) decreases deg(a(CHEBI:"amyloid-beta")) View Subject | View Object

As is known, the accumulation of frameshift ubiquitin-B (UBB) mutant protein UBB (+1) can block the 26S proteasome in cell lines, and then can reduce Aβ clearance (Hope et al. 2003) PubMed:29626319

Appears in Networks:

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

However, their dysfunction in AD due to some factors will reduce Aβ clearance PubMed:29626319

Appears in Networks:

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

However, recently, it has been reported that the expression and transport activity of P-gp are impaired in sporadic AD as a result of its ubiquitination, internalization, and proteasome-dependent degradation derived from Aβ40 (Chiu et al. 2015; Hartz et al. 2016), which will result in Aβ deposition PubMed:29626319

Appears in Networks:

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

Meanwhile, an animal experiment showed that IDE expression will descend with age and diabetes, then resulting in Aβ deposition (Kochkina et al. 2015) PubMed:29626319

Appears in Networks:

path(MESH:Sleep) decreases a(CHEBI:"amyloid-beta") View Subject | View Object

Later, an experiment on live mice using some special methods has also proved that natural sleep or sleep resulting from anesthesia can increase interstitial space by 60%, thereby speeding up the exchange of CSF-ISF and finally increasing the elimination of Aβ (Xie et al. 2013) PubMed:29626319

Appears in Networks:

a(CHEBI:Nilvadipine) decreases a(CHEBI:"amyloid-beta") View Subject | View Object

We have previously shown that the L-type calcium channel (LCC) antagonist nilvadipine reduces brain amyloid-β (Aβ) accumulation by affecting both Aβ production and Aβ clearance across the blood-brain barrier (BBB). PubMed:25331948

Appears in Networks:

a(HBP:"ACY-1215") decreases a(CHEBI:"amyloid-beta") View Subject | View Object

In the present study, we tested the potential of two selective HDAC6 inhibitors, tubastatin A and ACY-1215, to rescue cognitive deficits in a mouse model of AD. We found that both tubastatin A and ACY-1215 alleviated behavioral deficits, altered amyloid-β (Aβ) load, and reduced tau hyperphosphorylation in AD mice without obvious adverse effects. Our data suggested that tubastatin A and ACY-1215 not only promoted tubulin acetylation, but also reduced production and facilitated autophagic clearance of Aβ and hyperphosphorylated tau. PubMed:24844691

Appears in Networks:

a(HBP:"CM-414") decreases a(CHEBI:"amyloid-beta") View Subject | View Object

Here we report the discovery of a new first-in-class small-molecule (CM-414) that acts as a dual inhibitor of PDE5 and HDACs. We have used this compound as a chemical probe to validate this systems therapeutics strategy, where an increase in the activation of cAMP/cGMP-responsive element-binding protein (CREB) induced by PDE5 inhibition, combined with moderate HDAC class I inhibition, leads to efficient histone acetylation. This molecule rescued the impaired long-term potentiation evident in hippocampal slices from APP/PS1 mice. Chronic treatment of Tg2576 mice with CM-414 diminished brain Aβ and tau phosphorylation (pTau) levels, increased the inactive form of GSK3β, reverted the decrease in dendritic spine density on hippocampal neurons, and reversed their cognitive deficits, at least in part by inducing the expression of genes related to synaptic transmission. PubMed:27550730

Appears in Networks:

a(HBP:"SL-327") decreases a(CHEBI:"amyloid-beta") 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:

a(HBP:"Tau epitope, PHF1") positiveCorrelation a(CHEBI:"amyloid-beta") View Subject | View Object

Consistent with previous reports (11,34), treatment of rat hippocampal neurons with synthetic Aβ, prepared using a well-characterized procedure that enriches for Aβ oligomers (37), resulted in increased tau phosphorylation at the 12E8 sites (Fig. 2A), suggesting that Aβ treatment had activated MARK kinases. Increased phosphorylation of tau at a site recognized by the PHF-1 phospho-tau antibody was also observed (data not shown). PubMed:22156579

Appears in Networks:
Annotations
Uberon
hippocampal formation

a(HBP:"Tubastatin A") decreases a(CHEBI:"amyloid-beta") View Subject | View Object

In the present study, we tested the potential of two selective HDAC6 inhibitors, tubastatin A and ACY-1215, to rescue cognitive deficits in a mouse model of AD. We found that both tubastatin A and ACY-1215 alleviated behavioral deficits, altered amyloid-β (Aβ) load, and reduced tau hyperphosphorylation in AD mice without obvious adverse effects. Our data suggested that tubastatin A and ACY-1215 not only promoted tubulin acetylation, but also reduced production and facilitated autophagic clearance of Aβ and hyperphosphorylated tau. PubMed:24844691

Appears in Networks:

p(HBP:"Tau aggregates") positiveCorrelation a(CHEBI:"amyloid-beta") View Subject | View Object

In the HEK cell biosensor assay, tau from AD cases with plaques enhanced tau aggregates compared to tau from cases without plaques. In APP/PS1 cross with rTg4510 mice (P301L mutant human tau), tau seeding activity was threefold increased over the rTg4510 strain, without change in tau production or extracellular release. PubMed:28500862

Appears in Networks:

m(MIRBASE:"rno-mir-195") negativeCorrelation a(CHEBI:"amyloid-beta") View Subject | View Object

Chronic Brain hypoperfusion (CBH) elevates nuclear factor-kB (NF-kB), which binds with the promoter sequences of miR-195 and negatively regulates its expression. Down-regulated miR-195 up-regulates APP and BACE1 and increases Aß levels. Some Aß then enter the intracellular space and activate calpain, promoting the conversion of Cdk5/p35 to Cdk5/p25 and catalyzes the degradation of IkB (inhibitor of NF-?B)and directly phosphorylates Tau. Down-regulated miR-195 up-regulates p35, which provides the active substrates of p25 PubMed:26118667

Appears in Networks:

complex(p(HGNC:MAPT), p(INTERPRO:"Triosephosphate isomerase", pmod(NO))) positiveCorrelation a(CHEBI:"amyloid-beta") View Subject | View Object

Taupositive material was present in the immunoprecipitates indicating that tau becomes associated to nitroTPI in an Ab dose-dependent pattern (Fig. 5A).TPI and nitro-TPI were incubated with tau protein and samples were analysed by Atomic Force Microscopy (Fig. 7A–D) and TEM (Fig. 7F and G). Abundant paired helical filament-like structures were found in samples containing nitro-TPI plus tau PubMed:19251756

Appears in Networks:

p(MGI:Dyrk1a) negativeCorrelation a(CHEBI:"amyloid-beta") View Subject | View Object

Normalizing the gene dosage of Dyrk1A in the TS mouse rescued the density of senescent cells in the cingulate cortex, hippocampus and septum, prevented cholinergic neuron degeneration, and reduced App expression in the hippocampus, Aß load in the cortex and hippocampus, the expression of phosphorylated tau at the Ser202 residue in the hippocampus and cerebellum and the levels of total tau in the cortex, hippocampus and cerebellum. PubMed:29221819

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Annotations
Uberon
cerebral cortex
Uberon
hippocampal formation
MeSH
Alzheimer Disease
MeSH
Down Syndrome

composite(p(HGNC:MAPT, pmod(Ac, Lys, 163)), p(HGNC:MAPT, pmod(Ac, Lys, 280)), p(HGNC:MAPT, pmod(Ac, Lys, 281)), p(HGNC:MAPT, pmod(Ac, Lys, 369))) negativeCorrelation act(a(CHEBI:"amyloid-beta")) View Subject | View Object

We have used a knock-out/knock-in strategy in Drosophila to generate a strain with hTau inserted into the endogenous fly tau locus and expressed under the control of the endogenous fly tau promoter, thus avoiding potential toxicity due to genetic over-expression. hTau knock-in (KI) proteins were expressed at normal, endogenous levels, bound to fly microtubules and were post-translationally modified, hence displaying physiological properties. We used this new model to investigate the effects of acetylation on hTau toxicity in vivo. The simultaneous pseudo-acetylation of hTau at lysines 163, 280, 281 and 369 drastically decreased hTau phosphorylation and significantly reduced its binding to microtubules in vivo. These molecular alterations were associated with ameliorated amyloid beta toxicity. Our results indicate acetylation of hTau on multiple sites regulates its biology and ameliorates amyloid beta toxicity in vivo. PubMed:28855586

Appears in Networks:

p(HGNC:APP, pmod(HBP:polysumoylation)) decreases a(CHEBI:"amyloid-beta") View Subject | View Object

Increased protein sumoylation resulting from overexpression of SUMO-3 reduces Abeta production and reducing endogenous protein sumoylation with dominant-negative SUMO-3 mutants increases Abeta production. Mutant SUMO-3, K11R, which can only be monomerically conjugated to target proteins, has an opposite effect on Abeta generation to that by SUMO-3, which can form polymeric chains on target proteins. Polysumoylation reduces whereas monosumoylation or undersumoylation enhances Abeta generation. PubMed:12506199

Appears in Networks:

p(HGNC:APP, pmod(Sumo)) increases a(CHEBI:"amyloid-beta") View Subject | View Object

Increased protein sumoylation resulting from overexpression of SUMO-3 reduces Abeta production and reducing endogenous protein sumoylation with dominant-negative SUMO-3 mutants increases Abeta production. Mutant SUMO-3, K11R, which can only be monomerically conjugated to target proteins, has an opposite effect on Abeta generation to that by SUMO-3, which can form polymeric chains on target proteins. Polysumoylation reduces whereas monosumoylation or undersumoylation enhances Abeta generation. PubMed:12506199

Appears in Networks:

p(HGNC:APP, pmod(Sumo, Lys, 587)) decreases a(CHEBI:"amyloid-beta") View Subject | View Object

Lysines 587 and 595 of APP, immediately adjacent to the site of beta-secretase cleavage, are covalently modified by SUMO proteins in vivo. Sumoylation of these lysine residues is associated with decreased levels of Abeta aggregates. The results demonstrate that the SUMO E2 enzyme (ubc9) is present within the endoplasmic reticulum, indicating how APP, and perhaps other proteins that enter this compartment, can be sumoylated. PubMed:18675254

Appears in Networks:

p(HGNC:APP, pmod(Sumo, Lys, 595)) decreases a(CHEBI:"amyloid-beta") View Subject | View Object

Lysines 587 and 595 of APP, immediately adjacent to the site of beta-secretase cleavage, are covalently modified by SUMO proteins in vivo. Sumoylation of these lysine residues is associated with decreased levels of Abeta aggregates. The results demonstrate that the SUMO E2 enzyme (ubc9) is present within the endoplasmic reticulum, indicating how APP, and perhaps other proteins that enter this compartment, can be sumoylated. PubMed:18675254

Appears in Networks:

p(HGNC:HDAC3) increases a(CHEBI:"amyloid-beta") View Subject | View Object

HDAC3 overexpression in the hippocampus increases Aß levels, activates microglia, and decreases dendritic spine density in 6-month-old APP/PS1 mice. PubMed:28771976

Appears in Networks:
Annotations
Uberon
hippocampal formation

p(HGNC:MME) increases deg(a(CHEBI:"amyloid-beta")) View Subject | View Object

Neprilysin, a major Aß-degrading enzyme, was downregulated in DS patient-derived fibroblasts. Treatment with harmine, a DYRK1A inhibitor and gene knockdown of DYRK1A, upregulated neprilysin in fibroblasts. PubMed:28250274

Appears in Networks:
Annotations
MeSH
Down Syndrome

p(MGI:Bace1) positiveCorrelation a(CHEBI:"amyloid-beta") 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(MGI:Syk) positiveCorrelation a(CHEBI:"amyloid-beta") View Subject | View Object

We further validated Syk as a target-regulating Aβ by showing that pharmacological inhibition of Syk or down-regulation of Syk expression reduces Aβ production and increases the clearance of Aβ across the BBB mimicking (-)-nilvadipine effects. Moreover, treatment of transgenic mice overexpressing Aβ and transgenic Tau P301S mice with a selective Syk inhibitor respectively decreased brain Aβ accumulation and Tau hyperphosphorylation at multiple AD relevant epitopes. PubMed:25331948

Appears in Networks:

act(complex(GO:"NLRP3 inflammasome complex")) increases a(CHEBI:"amyloid-beta") View Subject | View Object

This finding was associated with spatial memory dysfunction and an increase in Abeta plaque deposition PubMed:28019679

Appears in Networks:
Annotations
Confidence
High
MeSH
Neurons
NeuroMMSigDB
Amyloidogenic subgraph

composite(a(CHEBI:"amyloid-beta"), p(HGNC:CD36)) hasComponent a(CHEBI:"amyloid-beta") View Subject | View Object

Appears in Networks:

composite(a(CHEBI:"amyloid-beta"), p(HGNC:CTSB)) hasComponent a(CHEBI:"amyloid-beta") View Subject | View Object

Appears in Networks:

p(HGNC:IDE) decreases a(CHEBI:"amyloid-beta") View Subject | View Object

The combined effect of the increased IDE production and phagocytic Abeta clearance reduced the cerebral Abeta load substantially, even at late life. Since immunohistochemistry found NLRP3 exclusively expressed in microglial cells, it has been concluded that the observed changes were entirely due to NLRP3 inflammasome modulation in these cells PubMed:28019679

Appears in Networks:
Annotations
Confidence
Medium
MeSH
Neurons
NeuroMMSigDB
Amyloidogenic subgraph
NeuroMMSigDB
Insulin signal transduction

g(HGNC:NLRP3) increases a(CHEBI:"amyloid-beta") View Subject | View Object

Deficiency of the NLRP3 gene reduces Aβ deposition and plays a protective role on memory and behavior (Heneka et al.,2013) PubMed:24561250

Appears in Networks:
Annotations
Confidence
High
NeuroMMSigDB
Amyloidogenic subgraph
NeuroMMSigDB
Caspase subgraph

p(HGNC:IL18) increases a(CHEBI:"amyloid-beta") View Subject | View Object

Pro-inflammatory IL-18 increases AD-associated A beta deposition in human neuron-like cells in culture [55]. IL-18 also increases the expression of glycogen synthase kinase 3 beta (GSK-3 beta ) and cyclin-dependent kinase 5, both of which are involved in hyperphos- phorylation of the tau protein [56]. PubMed:27314526

Appears in Networks:
Annotations
Confidence
High
MeSH
Neurons
MeSH
Alzheimer Disease
NeuroMMSigDB
Amyloidogenic subgraph
NeuroMMSigDB
Cyclin-CDK subgraph
NeuroMMSigDB
GSK3 subgraph
NeuroMMSigDB
Interleukin signaling subgraph
NeuroMMSigDB
Tau protein subgraph

sec(p(HGNC:IL1B)) increases a(CHEBI:"amyloid-beta") View Subject | View Object

NO can also bring about apoptosis of hippocampal neurons via caspase- 3 activity [50] whereas astrocyte-secreted IL-1 beta can increase the production of APP and A beta from neu- rons [51–53] (Fig. 1). PubMed:27314526

Appears in Networks:
Annotations
Confidence
Medium
MeSH
Neurons
MeSH
Alzheimer Disease
NeuroMMSigDB
Amyloidogenic subgraph
NeuroMMSigDB
Caspase subgraph
NeuroMMSigDB
Interleukin signaling subgraph
NeuroMMSigDB
Nitric oxide subgraph

p(HGNC:NLRP3) association a(CHEBI:"amyloid-beta") View Subject | View Object

In AD, microglial cells and astrocytes express NLRP3, which in turn can detect A beta plaques and act by secreting caspase-1 to activate IL-1 beta and IL- 18 [23–25]. PubMed:27314526

Appears in Networks:
Annotations
Confidence
Medium
MeSH
Alzheimer Disease
NeuroMMSigDB
Amyloidogenic subgraph
NeuroMMSigDB
Caspase subgraph
NeuroMMSigDB
Interleukin signaling subgraph

a(CHEBI:Anatabine) decreases a(CHEBI:"amyloid-beta") View Subject | View Object

Contrary to anatabine, (−)-nicotine and other nicotinic acetylcholine receptors agonists and antagonists do not inhibit Aβ production by 7W CHO cells (Fig. 3). PubMed:21958873

Appears in Networks:
Annotations
Experimental Factor Ontology (EFO)
CHO cell

a(CHEBI:Anatabine) decreases a(CHEBI:"amyloid-beta") View Subject | View Object

In addition, a significant decreased in plasma Aβ levels was observed in mice treated with anatabine consistent with an inhibition of Aβ production (Fig. 10). PubMed:21958873

Appears in Networks:
Annotations
MeSH
Plasma

a(CHEBI:nicotine) causesNoChange a(CHEBI:"amyloid-beta") View Subject | View Object

Contrary to anatabine, (−)-nicotine and other nicotinic acetylcholine receptors agonists and antagonists do not inhibit Aβ production by 7W CHO cells (Fig. 3). PubMed:21958873

Appears in Networks:
Annotations
Experimental Factor Ontology (EFO)
CHO cell

a(PUBCHEM:11957537) causesNoChange a(CHEBI:"amyloid-beta") View Subject | View Object

Contrary to anatabine, (−)-nicotine and other nicotinic acetylcholine receptors agonists and antagonists do not inhibit Aβ production by 7W CHO cells (Fig. 3). PubMed:21958873

Appears in Networks:
Annotations
Experimental Factor Ontology (EFO)
CHO cell

a(PUBCHEM:56972222) causesNoChange a(CHEBI:"amyloid-beta") View Subject | View Object

Contrary to anatabine, (−)-nicotine and other nicotinic acetylcholine receptors agonists and antagonists do not inhibit Aβ production by 7W CHO cells (Fig. 3). PubMed:21958873

Appears in Networks:
Annotations
Experimental Factor Ontology (EFO)
CHO cell

a(PUBCHEM:71311633) causesNoChange a(CHEBI:"amyloid-beta") View Subject | View Object

Contrary to anatabine, (−)-nicotine and other nicotinic acetylcholine receptors agonists and antagonists do not inhibit Aβ production by 7W CHO cells (Fig. 3). PubMed:21958873

Appears in Networks:
Annotations
Experimental Factor Ontology (EFO)
CHO cell

p(HBP:"alpha-Bungarotoxin") causesNoChange a(CHEBI:"amyloid-beta") View Subject | View Object

Contrary to anatabine, (−)-nicotine and other nicotinic acetylcholine receptors agonists and antagonists do not inhibit Aβ production by 7W CHO cells (Fig. 3). PubMed:21958873

Appears in Networks:
Annotations
Experimental Factor Ontology (EFO)
CHO cell

a(CHEBI:Anatabine) decreases a(CHEBI:"amyloid-beta") View Subject | View Object

We observed that anatabine reduces brain Aβ burden both in the cortex and the hippocampus of Tg PS1/APPswe mice using immunostaining with the antibody 4G8 which recognizes Aβ (Fig 8A and 8B). PubMed:26010758

Appears in Networks:
Annotations
MeSH
Cerebral Cortex
MeSH
Hippocampus
MeSH
Alzheimer Disease

bp(GO:"one-carbon metabolic process") decreases act(a(CHEBI:"amyloid-beta")) View Subject | View Object

Remarkably, impairment of one-carbon metabolism in animal models can reproduce AD-like pathological features: accumulation of P-tau (Sontag et al.,2007; Zhang et al.,2008; Wei et al.,2011); enhanced amyloidogenesis (Pacheco-Quinto et al.,2006; Zhang et al.,2009; Zhuo et al.,2010; Zhuo and Pratico,2010); increased phosphorylation of APP at the regulatory Thr-668 site (Sontag et al.,2007; Zhang et al.,2009); increased sensitivity to amyloid toxicity (Kruman et al.,2002); and cognitive impairment (Bernardo et al.,2007; Wei et al.,2011; Rhodehouse et al., 2013). PubMed:24653673

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bp(GO:"axonal transport") association a(CHEBI:"amyloid-beta") View Subject | View Object

The amount of Aβ produced could be altered by delayed axonal transport, as well as the precise species of metabolites of APPproduced— e.g., Aβ40 or 42, monomeric Aβ, or Aβ-oligomers or Aβ-derived diffusible ligands (ADDLs) (Lambert et al., 1998; Walsh et al., 2000). PubMed:12428809

Appears in Networks:

a(CHEBI:sirolimus) decreases a(CHEBI:"amyloid-beta") View Subject | View Object

For instance, rapamycin, an inhibitor of the Ser/Thr protein kinase mammalian target of rapamycin (mTOR), improves cognitive function and reduces Aβ in AD mouse model by enhancing autophagic flux [23]. PubMed:29758300

Appears in Networks:

a(CHEBI:sirolimus) decreases a(CHEBI:"amyloid-beta") View Subject | View Object

For instance, while accumulation of Aβ activates the mTOR signaling pathway and subsequently blocks macroautophagy, rapamycin reduces the Aβ load by enhancing macroautophagy [32] PubMed:29758300

Appears in Networks:

bp(GO:macroautophagy) regulates a(CHEBI:"amyloid-beta") View Subject | View Object

Increased Aβ generation and accumulation in lysosomes suggest that Aβ metabolism, at least partially, is regulated by macroautophagy [3,14,32–34]. PubMed:29758300

Appears in Networks:
Annotations
MeSH
Lysosomes

bp(GO:macroautophagy) negativeCorrelation a(CHEBI:"amyloid-beta") View Subject | View Object

For instance, while accumulation of Aβ activates the mTOR signaling pathway and subsequently blocks macroautophagy, rapamycin reduces the Aβ load by enhancing macroautophagy [32] PubMed:29758300

Appears in Networks:

bp(GO:macroautophagy) increases deg(a(CHEBI:"amyloid-beta")) View Subject | View Object

In line with this, reduced Beclin 1 levels, as seen in AD models [16], increase the levels of intracellular and extracellular Aβ peptides, supporting the role of macroautophagy in the generation and degradation of Aβ [33,35]. PubMed:29758300

Appears in Networks:

bp(GO:macroautophagy) regulates a(CHEBI:"amyloid-beta") View Subject | View Object

In line with this, reduced Beclin 1 levels, as seen in AD models [16], increase the levels of intracellular and extracellular Aβ peptides, supporting the role of macroautophagy in the generation and degradation of Aβ [33,35]. PubMed:29758300

Appears in Networks:

bp(GO:macroautophagy) increases sec(a(CHEBI:"amyloid-beta")) View Subject | View Object

Compromised macroautophagy, via the genetic suppression of Atg7, leads to the blockade of Aβ secretion and contributes to the subsequent diminution in extracellular Aβ plaque load PubMed:29758300

Appears in Networks:

bp(GO:macroautophagy) increases sec(a(CHEBI:"amyloid-beta")) View Subject | View Object

This inhibition of Aβ secretion during macroautophagy deficiency results in aberrant cytosolic accumulation of Aβ, which ultimately evokes neurodegeneration accompanied with memory loss. PubMed:29758300

Appears in Networks:

act(complex(GO:"TOR complex")) positiveCorrelation a(CHEBI:"amyloid-beta") View Subject | View Object

For instance, while accumulation of Aβ activates the mTOR signaling pathway and subsequently blocks macroautophagy, rapamycin reduces the Aβ load by enhancing macroautophagy [32] PubMed:29758300

Appears in Networks:

p(HGNC:SORL1) negativeCorrelation a(CHEBI:"amyloid-beta") View Subject | View Object

Identified as a candidate susceptibility gene for AD by GWAS [116], reduced level of SORL1 has been consistently correlated with brain Aβ levels [118,119]. PubMed:29758300

Appears in Networks:

g(HBP:"APOE e4") regulates deg(a(CHEBI:"amyloid-beta")) View Subject | View Object

For instance, ApoE4–an important determinant of cholesterol metabolism and the strongest genetic risk factor for sporadic AD – regulates Aβ degradation [77]. PubMed:29758300

Appears in Networks:

p(HGNC:BIN1) decreases a(CHEBI:"amyloid-beta") View Subject | View Object

Suppression of BIN1 disrupts cellular trafficking of BACE1 and reduces BACE1 lysosomal degradation, leading to increased Aβ production [103]. PubMed:29758300

Appears in Networks:

p(HGNC:PICALM) positiveCorrelation a(CHEBI:"amyloid-beta") View Subject | View Object

Overexpression of PICALM in APP/PS1 mice substantially elevates Aβ levels, whereas knockdown reduces the Aβ plaque load, respectively [98] PubMed:29758300

Appears in Networks:

p(HGNC:PICALM) increases a(CHEBI:"amyloid-beta") View Subject | View Object

A recent line of work revealed Aβ-promoting function of PICALM by demonstrating that PICALM depletion decreased Aβ generation through disrupting clathrin-mediated endocytosis and internalization of γ-secretase [99,100]. PubMed:29758300

Appears in Networks:

p(HGNC:PICALM) increases tloc(a(CHEBI:"amyloid-beta"), fromLoc(MESH:"Endothelial Cells"), toLoc(MESH:Blood)) View Subject | View Object

PICALM may also promote amyloid clearance from the brain by internalizing Aβ into endothelial cells and ultimately into to the bloodstream [101] PubMed:29758300

Appears in Networks:

path(HBP:"mitochondrial dysfunction") increases a(CHEBI:"amyloid-beta") View Subject | View Object

Previous studies demonstrate impaired mitochondrial function preceding the accumulation of hallmark proteins in AD, such as Aβ [123,124] and tau [125]. PubMed:29758300

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MeSH
Alzheimer Disease

rxn(reactants(a(MESH:Sphingomyelins)), products(a(CHEBI:ceramide))) increases a(CHEBI:"amyloid-beta") View Subject | View Object

The finding of reduced Aβ generation when conversion of sphingomyelin to ceramide is blocked further substantiates the crucial involvement of sphingolipids in Aβ metabolism through modulation of γ-secretase [81,82] PubMed:29758300

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a(CHEBI:"amyloid-beta polypeptide 42") positiveCorrelation a(CHEBI:"amyloid-beta") View Subject | View Object

Consistent with these findings, strong overexpression of human Ab42, but not Ab40, in Drosophila neurons induces age-related accumulation of Ab in autolysosomes and neurotoxicity (Ling et al. 2009). PubMed:22908190

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MeSH
Neurons

a(CHEBI:sirolimus) decreases a(CHEBI:"amyloid-beta") View Subject | View Object

Peripheral administration of rapamycin to strongly stimulate autophagy substantially reduces amyloid deposition and tau pathology in both APPand triple transgenic mouse models of AD pathology (Caccamo et al. 2010; Spilman et al. 2010; Tian et al. 2011) PubMed:22908190

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a(MESH:Cathepsins) regulates deg(a(CHEBI:"amyloid-beta")) View Subject | View Object

Although less well studied as “Ab degrading proteases” than the zinc metallopeptidase family (Guenette 2003; Eckman et al. 2005), cathepsins are considered an important route for Ab/amyloid clearance (Mueller-Steiner et al. 2006; Nixon 2007; Butler et al. 2011) and human neurons may be particularly dependent on this mechanism (LeBlanc et al. 1999; reviewed in Saido and Leissring 2011). PubMed:22908190

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bp(GO:"lysosomal protein catabolic process") increases deg(a(CHEBI:"amyloid-beta")) View Subject | View Object

Chronic low-level stimulation of autophagy through peripheral administration of rapamycin or other agents (Tian et al. 2011), or enhancing lysosomal proteolysis selectively (Sun et al. 2008; Yang et al. 2011), can markedly diminish Ab levels and amyloid load in APP transgenic mice, underscoring the importance of lysosomal clearance of Ab. PubMed:22908190

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bp(GO:"lysosomal protein catabolic process") increases deg(a(CHEBI:"amyloid-beta")) View Subject | View Object

Endocytic pathway up-regulation in AD stemming in part from pathological rab 5 activation generates higher levels of Ab (Mathews et al. 2002; Grbovic et al. 2003) that must be cleared in part by lysosomes. PubMed:22908190

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bp(GO:"lysosomal protein catabolic process") decreases a(CHEBI:"amyloid-beta") View Subject | View Object

Stimulating lysosomal proteolytic efficiency in the TgCRND8 APP mouse model by deleting an endogenous inhibitor of lysosomal cysteine proteases (cystatin B) rescues lysosomal pathology, eliminates abnormal autolysosomal accumulation of autophagy substrates, including Ab, decreases Ab and amyloid deposition, and ameliorates learning and memory deficits (Yang et al. 2011) PubMed:22908190

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bp(GO:autophagy) increases deg(a(CHEBI:"amyloid-beta")) View Subject | View Object

Chronic low-level stimulation of autophagy through peripheral administration of rapamycin or other agents (Tian et al. 2011), or enhancing lysosomal proteolysis selectively (Sun et al. 2008; Yang et al. 2011), can markedly diminish Ab levels and amyloid load in APP transgenic mice, underscoring the importance of lysosomal clearance of Ab. PubMed:22908190

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bp(GO:endocytosis) positiveCorrelation a(CHEBI:"amyloid-beta") View Subject | View Object

Endocytic pathway up-regulation in AD stemming in part from pathological rab 5 activation generates higher levels of Ab (Mathews et al. 2002; Grbovic et al. 2003) that must be cleared in part by lysosomes. PubMed:22908190

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bp(GO:endocytosis) positiveCorrelation a(CHEBI:"amyloid-beta") View Subject | View Object

Pathological rab5 activation, which in Down syndrome is dependent on bCTF generation (Jiang et al. 2010), can up-regulate endocytosis in a manner functionally equivalent to the elevated endocytosis associated with increased synaptic activity, which is considered a source of Ab generation (Cirrito et al. 2008). PubMed:22908190

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MeSH
Down Syndrome

act(complex(GO:"proteasome complex")) negativeCorrelation a(CHEBI:"amyloid-beta") View Subject | View Object

Thus, the accumulation of tau and of Ab, forming the two major protein lesions of AD, impairs proteasome activity in vivo. PubMed:22908190

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MeSH
Alzheimer Disease

g(HBP:"APOE e4") increases act(a(CHEBI:"amyloid-beta")) View Subject | View Object

Expression of the ApoE epsilon 4 allele, but not ApoE epsilon 3, in mice administered a neprilysin inhibitor increases Ab immunoreactivity in lysosomes and causes neurodegeneration of hippocampal CA1, entorhinal,and septal neurons (Belinson et al. 2008). PubMed:22908190

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MeSH
Lysosomes

act(p(HGNC:RAB5A)) increases a(CHEBI:"amyloid-beta") View Subject | View Object

Endocytic pathway up-regulation in AD stemming in part from pathological rab 5 activation generates higher levels of Ab (Mathews et al. 2002; Grbovic et al. 2003) that must be cleared in part by lysosomes. PubMed:22908190

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deg(p(HGNC:APP)) association a(CHEBI:"amyloid-beta") View Subject | View Object

Recent evidence suggests that the autophagic turnover of amyloid beta precursor protein (APP) may underlie the generation of toxic amyloid-β species [61]. PubMed:18930136

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a(CHEBI:"2-[[7-(3,4-dimethoxyphenyl)-5-imidazo[1,2-c]pyrimidinyl]amino]-3-pyridinecarboxamide") decreases a(CHEBI:"amyloid-beta") View Subject | View Object

We found that Syk inhibition with the selective Syk inhibitor BAY61-3606 suppresses Aβ production in 7W CHO cells overexpressing APP (Fig. 6A). PubMed:25331948

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a(CHEBI:"2-[[7-(3,4-dimethoxyphenyl)-5-imidazo[1,2-c]pyrimidinyl]amino]-3-pyridinecarboxamide") increases tloc(a(CHEBI:"amyloid-beta"), fromLoc(GO:intracellular), toLoc(MESH:Plasma)) View Subject | View Object

We show that the selective Syk inhibitor BAY61-3606 stimulates the transport of Aβ across the BBB in vitro mimicking the biological activity of (-)-nilvadipine in this model (Fig. 7A). PubMed:25331948

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MeSH
Blood-Brain Barrier

a(CHEBI:Nilvadipine) decreases a(CHEBI:"amyloid-beta") View Subject | View Object

Following 24 h of treatment with the pure enantiomers or the racemic mixture of nilvadipine, a dose-dependent inhibition of Aβ production was observed (Fig. 1A). PubMed:25331948

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a(CHEBI:Nilvadipine) decreases a(CHEBI:"amyloid-beta") View Subject | View Object

In addition, a reduction in BACE-1 protein levels was observed following treatment of HEK293 cells with (-)-nilvadipine or racemic nilvadipine (Fig. 1D) further suggesting that the inhibition of Aβ production observed following nilvadipine treatment is mediated in part by a reduction of BACE-1 expression. PubMed:25331948

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a(CHEBI:Nilvadipine) decreases a(CHEBI:"amyloid-beta") View Subject | View Object

We tested the effect of an acute treatment with (-)-nilvadipine or (+)-nilvadipine on brain Aβ levels using Tg PS1/APPsw mice, and we observed that both (-)-nilvadipine and (+)-nilvadipine acutely reduced brain Aβ levels with similar potency (Fig. 2, C and D). PubMed:25331948

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MeSH
Brain

a(PUBCHEM:71656932) causesNoChange a(CHEBI:"amyloid-beta") View Subject | View Object

Wetested a selective BTK inhibitor (BTK inhibitor III, 1-(3-(4-amino-3-(4-phenyloxy phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)prop-2-en-1-one, N-acryloyl-(3-(4-amino-3-(4-phenyloxyphenyl)- 1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine) on Aβ production, and we found that this compound was unable to significantly inhibit Aβ production (data not shown) suggesting that the Aβ-lowering properties of nilvadipine are not mediated via an inhibition of BTK. PubMed:25331948

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p(HGNC:SYK) increases a(CHEBI:"amyloid-beta") View Subject | View Object

We found that Syk inhibition with the selective Syk inhibitor BAY61-3606 suppresses Aβ production in 7W CHO cells overexpressing APP (Fig. 6A). PubMed:25331948

Appears in Networks:

act(p(HGNC:SYK)) increases a(CHEBI:"amyloid-beta") View Subject | View Object

Interestingly, Aβ production in 7W CHO cells transfected with SYK shRNA compared with 7W CHO cells (Fig. 6C) was significantly reduced, further demonstrating the involvement of Syk in the regulation of Aβ production. PubMed:25331948

Appears in Networks:

act(p(HGNC:SYK)) decreases tloc(a(CHEBI:"amyloid-beta"), fromLoc(GO:intracellular), toLoc(MESH:Plasma)) View Subject | View Object

We show that the selective Syk inhibitor BAY61-3606 stimulates the transport of Aβ across the BBB in vitro mimicking the biological activity of (-)-nilvadipine in this model (Fig. 7A). PubMed:25331948

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Annotations
MeSH
Blood-Brain Barrier

p(HGNC:BACE1) increases a(CHEBI:"amyloid-beta") View Subject | View Object

In addition, a reduction in BACE-1 protein levels was observed following treatment of HEK293 cells with (-)-nilvadipine or racemic nilvadipine (Fig. 1D) further suggesting that the inhibition of Aβ production observed following nilvadipine treatment is mediated in part by a reduction of BACE-1 expression. PubMed:25331948

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p(HGNC:CHRNA7) regulates act(a(CHEBI:"amyloid-beta")) View Subject | View Object

AD brains show an upregulation of CHRNA7 (acr-14 homolog in humans) (84), where it may mediate the Ab-induced tau pathology (85). PubMed:29191965

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MeSH
Brain

tloc(p(HGNC:MAPT), fromLoc(GO:axon), toLoc(MESH:"Dendritic Spines")) regulates act(a(CHEBI:"amyloid-beta")) View Subject | View Object

In cultured neurons, missorted dendritic tau may mediate toxicity that is induced by Aβ or other stressors by promoting the translocation of tubulin tyrosine ligase-like enzyme 6 (TTLL6) into dendrites, and the severing of microtubules by spastin PubMed:26631930

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p(HGNC:MAPT) increases act(a(CHEBI:"amyloid-beta")) View Subject | View Object

In addition, dendritic tau could serve as a protein scaffold to deliver the kinase FYN to postsynaptic sites, where FYN phosphorylates subunit 2 of the NMDA receptor (NR2B; also known as GluN2B), resulting in the stabilization of the interaction of this receptor interaction with postsynaptic density protein 95 (PSD95; also known as DLG4), potentiating glutamatergic signalling and thereby enhancing Aβ toxicity. PubMed:26631930

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MeSH
Dendritic Spines

complex(p(HGNC:DLG4), p(HGNC:FYN)) increases act(a(CHEBI:"amyloid-beta")) View Subject | View Object

In addition, dendritic tau could serve as a protein scaffold to deliver the kinase FYN to postsynaptic sites, where FYN phosphorylates subunit 2 of the NMDA receptor (NR2B; also known as GluN2B), resulting in the stabilization of the interaction of this receptor interaction with postsynaptic density protein 95 (PSD95; also known as DLG4), potentiating glutamatergic signalling and thereby enhancing Aβ toxicity. PubMed:26631930

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MeSH
Dendritic Spines

tloc(p(HGNC:TTLL6), fromLoc(GO:axon), toLoc(MESH:"Dendritic Spines")) increases act(a(CHEBI:"amyloid-beta")) View Subject | View Object

In cultured neurons, missorted dendritic tau may mediate toxicity that is induced by Aβ or other stressors by promoting the translocation of tubulin tyrosine ligase-like enzyme 6 (TTLL6) into dendrites, and the severing of microtubules by spastin PubMed:26631930

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g(HGNC:"MIR153-1") decreases a(CHEBI:"amyloid-beta") View Subject | View Object

Downregulation of miR‐153 increases the expression of APP and eventually, the production of β‐ameloid is promoted, increasing the risk of AD PubMed:30663117

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MeSH
Alzheimer Disease

p(HGNC:CAMKK2) increases act(a(CHEBI:"amyloid-beta")) View Subject | View Object

By activating the CAMMK2 pathway, the β‐ameloid can aid in the phosphorylation of tau proteins and eventually trigger tangles neurofibrillary. PubMed:30663117

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MeSH
Alzheimer Disease

r(HGNC:"BACE1-AS") increases a(CHEBI:"amyloid-beta") View Subject | View Object

It has been reported that downregulation of BACE1‐AS reduces the amount of β‐ameloid and plaques PubMed:30663117

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MeSH
Alzheimer Disease

a(PUBCHEM:441923) decreases a(CHEBI:"amyloid-beta") View Subject | View Object

A levels in the brain of mice were consider-ably reduced with treatment of ginsenoside Re\Rg3\Rg1 (25 mg/kg)[224]. PubMed:29179999

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p(HGNC:RELA) increases a(CHEBI:"amyloid-beta") View Subject | View Object

The results showed that NF-kB p65 expression significantly increased total Ab protein concentration by 134.90¡5.74% in SAS1 cells, a stable SH-SY5Y cell stably expressing Swedish mutant APP695 (Sun et al. 2006a) (p<0.0001) (Fig. 5j). PubMed:21329555

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Experimental Factor Ontology (EFO)
SH-SY5Y

p(HGNC:NFKBIA) decreases a(CHEBI:"amyloid-beta") View Subject | View Object

IkBa expression plasmid was also transfected into SAS1 cells and IkBa transfection reduced Ab protein levels to 92.24¡2.68% (p<0.05). PubMed:21329555

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Annotations
Experimental Factor Ontology (EFO)
SH-SY5Y

bp(MESH:"Oxidative Stress") association a(CHEBI:"amyloid-beta") View Subject | View Object

Amyloid-β induced apoptosis has also been ascribed to dyshomeostasis of intracellular Ca2+ and oxidative stress [106-108], two critical biochemical derangements known to activate NF-κB PubMed:28745240

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MeSH
Alzheimer Disease

act(complex(GO:"NF-kappaB complex")) increases sec(a(CHEBI:"amyloid-beta")) View Subject | View Object

Multiple studies have cogently shown that the inhibition of NF-κB activity results in the mitigation of secreted Amyloid-β by cultured cells in vitro PubMed:28745240

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MeSH
Alzheimer Disease

act(complex(GO:"NF-kappaB complex")) increases a(CHEBI:"amyloid-beta") View Subject | View Object

NF-κB is also widely implicated in the engenderment of Amyloid-β in vivo in a multitude of mouse models PubMed:28745240

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MeSH
Alzheimer Disease

complex(GO:"NF-kappaB complex") regulates a(CHEBI:"amyloid-beta") View Subject | View Object

A multitude of studies have demonstrated that NF-κB directly regulates the transcription and expression of BACE1, thereby eliciting profound effects on AβPP processing and engenderment of Amyloid-β PubMed:28745240

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Annotations
MeSH
Alzheimer Disease

complex(GO:"NF-kappaB complex") regulates a(CHEBI:"amyloid-beta") View Subject | View Object

Indeed, Checler and colleagues have shown in a recent study that, NF-κB mediates the Amyloid-β – induced increase in expression of AβPP in HEK293 cells PubMed:28745240

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Experimental Factor Ontology (EFO)
HEK293
MeSH
Alzheimer Disease

a(CHEBI:"(+)-artemisinin") decreases a(CHEBI:"amyloid-beta") View Subject | View Object

The expression of A was lowered by artemisinin through inhibition of the activity of NALP3 inflammasome in APPswe/PS1E9 transgenic mice [241]. PubMed:29179999

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MeSH
Alzheimer Disease

a(CHEBI:"alpha-tocopherol") decreases a(CHEBI:"amyloid-beta") View Subject | View Object

Reduction of A expression and cytotoxic-ity stimulated by A in neuroblastoma cells and the inhibition of inflammatory cytokines, ROS and NO in microglial cells were detected upon treatment with -tocopherol [210]. PubMed:29179999

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Cell Ontology (CL)
microglial cell

a(CHEBI:"alpha-tocopherol") decreases a(CHEBI:"amyloid-beta") View Subject | View Object

Oxidative stress and A expression were suppressed with -tocopherol in mouse model. PubMed:29179999

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a(CHEBI:"gallic acid") decreases act(a(CHEBI:"amyloid-beta")) View Subject | View Object

A-activated NF-B activity and the expression of cytokines were attenuated with gallic acid in microglial cells y decreased acetylation of RelA, which subsequently reduced A-activated neu-rotoxicity [164]. PubMed:29179999

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Annotations
Cell Ontology (CL)
microglial cell

a(CHEBI:Anatabine) decreases a(CHEBI:"amyloid-beta") View Subject | View Object

Anatabine lowered NF-B activation by inhibiting A production in vitro [195]. PubMed:29179999

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a(CHEBI:Geniposide) decreases a(CHEBI:"amyloid-beta") View Subject | View Object

Geniposide considerably suppressed RAGE-related signaling such as ERK and IB/NF-B, the expression of TNF-, IL-1 and cerebral A accumulation in vivo[245] PubMed:29179999

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MeSH
Cerebral Cortex

a(PUBCHEM:3086007) decreases a(CHEBI:"amyloid-beta") View Subject | View Object

A levels in the brain of mice were consider-ably reduced with treatment of ginsenoside Re\Rg3\Rg1 (25 mg/kg)[224]. PubMed:29179999

Appears in Networks:

a(PUBCHEM:441921) decreases a(CHEBI:"amyloid-beta") View Subject | View Object

A levels in the brain of mice were consider-ably reduced with treatment of ginsenoside Re\Rg3\Rg1 (25 mg/kg)[224]. PubMed:29179999

Appears in Networks:

a(PUBCHEM:9918693) decreases a(CHEBI:"amyloid-beta") View Subject | View Object

A levels in the brain of mice were consider-ably reduced with treatment of ginsenoside Re\Rg3\Rg1 (25 mg/kg)[224]. PubMed:29179999

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a(CHEBI:ibuprofen) decreases a(CHEBI:"amyloid-beta") View Subject | View Object

Further- more, naproxen and ibuprofen and perhaps other NSAIDs, can block the inflammation-induced BACE1 transcription and Aβ production [52,87]. PubMed:27288790

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Annotations
MeSH
Cerebral Cortex
MeSH
Hippocampus

a(CHEBI:naproxen) decreases a(CHEBI:"amyloid-beta") View Subject | View Object

Further- more, naproxen and ibuprofen and perhaps other NSAIDs, can block the inflammation-induced BACE1 transcription and Aβ production [52,87]. PubMed:27288790

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Annotations
MeSH
Cerebral Cortex
MeSH
Hippocampus

a(PUBCHEM:6440944) decreases a(CHEBI:"amyloid-beta") View Subject | View Object

What's more, DLPC complete- ly abolishes TNF-α and H 2 O 2 induced neuronal tau phosphorylation, re- duces cellular APP levels and Aβ expression and secretion in SH-SY5Y cells [91,92] (Table 1). PubMed:27288790

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Experimental Factor Ontology (EFO)
SH-SY5Y
MeSH
Cerebral Cortex
MeSH
Hippocampus

a(PUBCHEM:6440944) decreases sec(a(CHEBI:"amyloid-beta")) View Subject | View Object

What's more, DLPC complete- ly abolishes TNF-α and H 2 O 2 induced neuronal tau phosphorylation, re- duces cellular APP levels and Aβ expression and secretion in SH-SY5Y cells [91,92] (Table 1). PubMed:27288790

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Experimental Factor Ontology (EFO)
SH-SY5Y
MeSH
Cerebral Cortex
MeSH
Hippocampus

act(complex(GO:"NF-kappaB complex")) regulates a(CHEBI:"amyloid-beta") View Subject | View Object

Under physiological conditions activation of NF-κB by endogenous Aβ reduces βAPP, BACE1 and the γ-secretase activity, thereby lowering Aβ processing and facilitating Aβ homeostasis PubMed:25652642

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act(complex(GO:"NF-kappaB complex")) positiveCorrelation a(CHEBI:"amyloid-beta") View Subject | View Object

However in AD, exposure to high Aβ concentrations upregulates NF-κB activation increasing βAPP and Aβ processing, precipitating a feed-back loop that favor exacerbated Aβ production PubMed:25652642

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Annotations
MeSH
Alzheimer Disease

complex(a(GO:"NF-kappaB complex"), p(HGNC:REL)) decreases act(a(CHEBI:"amyloid-beta")) View Subject | View Object

In metabotrophic glutamate receptor-5 (mGlu5) agonist pretreated primary cortical neurons or neuroblastoma cells, Aβ induced toxicity was suppressed by selective activation of c-rel containing NF-κB dimers and transactivation of anti-apoptotic genes, Mn-SOD and Bcl-Xl [26] (Figs 1B, 2A) PubMed:25652642

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Annotations
MeSH
Neurons
MeSH
Alzheimer Disease

act(p(HGNC:BCL2L1)) decreases act(a(CHEBI:"amyloid-beta")) View Subject | View Object

In metabotrophic glutamate receptor-5 (mGlu5) agonist pretreated primary cortical neurons or neuroblastoma cells, Aβ induced toxicity was suppressed by selective activation of c-rel containing NF-κB dimers and transactivation of anti-apoptotic genes, Mn-SOD and Bcl-Xl [26] (Figs 1B, 2A) PubMed:25652642

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Annotations
MeSH
Neurons
MeSH
Alzheimer Disease

act(p(HGNC:SOD2)) decreases act(a(CHEBI:"amyloid-beta")) View Subject | View Object

In metabotrophic glutamate receptor-5 (mGlu5) agonist pretreated primary cortical neurons or neuroblastoma cells, Aβ induced toxicity was suppressed by selective activation of c-rel containing NF-κB dimers and transactivation of anti-apoptotic genes, Mn-SOD and Bcl-Xl [26] (Figs 1B, 2A) PubMed:25652642

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Annotations
MeSH
Neurons
MeSH
Alzheimer Disease

a(CHEBI:clozapine) decreases a(CHEBI:"amyloid-beta") View Subject | View Object

Chronic clozapine treatment (20 mg/kg/day) reduces Abeta deposition PubMed:30061532

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MeSH
Frontal Lobe

act(p(HGNC:MTOR)) increases a(CHEBI:"amyloid-beta") View Subject | View Object

For instance, an increased mTOR activity correlates with accumulation of Abeta and hyperphosphorylated tau in AD brains PubMed:30061532

Appears in Networks:
Annotations
MeSH
Brain
MeSH
Alzheimer Disease

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

In addition, most DLB patients show most features of AD (i.e., hyperphosphorylated tau deposits and A beta) to various extents PubMed:30061532

Appears in Networks:

Out-Edges 245

tloc(a(CHEBI:"amyloid-beta"), fromLoc(MESH:Blood), toLoc(MESH:"Cerebrospinal Fluid")) regulates deg(a(CHEBI:"amyloid-beta")) View Subject | View Object

By contrast, the parenchyma of the CNS is devoid of lymphatic vasculature2; in the brain, removal of cellular debris and toxic molecules, such as amyloid-β peptides, is mediated by a combination of transcellular transport mechanisms across the blood−brain and blood−cerebrospinal fluid (CSF) barriers7–9, phagocytosis and digestion by resident microglia and recruited monocytes and/or macrophages10,11, as well as CSF influx and ISF efflux through a paravascular (glymphatic) route12–14 PubMed:30046111

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Annotations
Confidence
High
MeSH
Brain

a(CHEBI:"amyloid-beta") negativeCorrelation act(a(MESH:"Lymphatic Vessels")) View Subject | View Object

Analysis of lymphoid and myeloid cell populations in the meninges (Extended Data Fig. 9d) demonstrated a significant increase in the number of macrophages upon lymphatic ablation compared to both control groups (Extended Data Fig. 9e), which might be correlated with increased amyloid-β deposition and inflammation in the meninges PubMed:30046111

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Confidence
High
MeSH
Meninges

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

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

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Confidence
Medium
MeSH
Brain
MeSH
Parenchymal Tissue

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

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

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Confidence
Medium
MeSH
Dura Mater
MeSH
Superior Sagittal Sinus

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

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

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Confidence
Medium
MeSH
Meninges
MeSH
Alzheimer Disease

a(CHEBI:"amyloid-beta") association a(MESH:Macrophages) View Subject | View Object

Macrophages in the dura of cases with Alzheimer’s disease were also found in close proximity to amyloid-β deposits (Fig. 3l) PubMed:30046111

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Confidence
High
MeSH
Dura Mater
MeSH
Alzheimer Disease

a(CHEBI:"amyloid-beta") increases bp(HBP:HBP00061) View Subject | View Object

Aβ synaptoxicity is Dkk1-dependent12,24 and also appears to be APP-dependent25. PubMed:30232325

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Confidence
High

a(CHEBI:"amyloid-beta") increases complex(GO:"neurofibrillary tangle") View Subject | View Object

These Aβ deposits lead to subsequent molecular and cellular alterations, such as NTFs, neuronal dystrophy, or microgliosis, i.e., pathological events that are closer to dementia and more relevant to neuronal dysfunction. PubMed:29196815

Appears in Networks:
Annotations
Confidence
Medium

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

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

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Confidence
Medium

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

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

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Annotations
Confidence
High

a(CHEBI:"amyloid-beta") increases bp(GO:"positive regulation of neuron apoptotic process") View Subject | View Object

The presence of amyloid deposits, as the main factor leading to damage of the nerve tissue (amyloid hypothesis) has been postulated for over 25 years (recently reviewed in Selkoe and Hardy 2016). PubMed:29196815

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Confidence
High

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

These Aβ deposits lead to subsequent molecular and cellular alterations, such as NTFs, neuronal dystrophy, or microgliosis, i.e., pathological events that are closer to dementia and more relevant to neuronal dysfunction. PubMed:29196815

Appears in Networks:
Annotations
Confidence
Medium

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

These Aβ deposits lead to subsequent molecular and cellular alterations, such as NTFs, neuronal dystrophy, or microgliosis, i.e., pathological events that are closer to dementia and more relevant to neuronal dysfunction. PubMed:29196815

Appears in Networks:
Annotations
Confidence
Medium

a(CHEBI:"amyloid-beta") increases bp(GO:"cell adhesion") View Subject | View Object

Interestingly, because the RHDS sequence is contained within the N terminus of Aβ, similar cell adhesion-promoting properties have also been attributed to the Aβ peptide itself. PubMed:18650430

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Confidence
Medium

a(CHEBI:"amyloid-beta") increases path(MESH:"Plaque, Amyloid") View Subject | View Object

Extracellular neuritic plaques are deposits of differently sized small peptides called beta-amyloid (Abeta) that are derived via sequential proteolytic cleavages of the b-amyloid precursor protein (APP) [6] PubMed:21214928

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Annotations
Confidence
High

a(CHEBI:"amyloid-beta") increases path(MESH:"Plaque, Amyloid") View Subject | View Object

In Down Syndrome (DS) patients, the accumulation of intracellular Abeta precedes extracellular plaque formation [148] and the level of intraneuronal Ab decreases as the extracellular Abeta plaques accumulate [149] PubMed:21214928

Appears in Networks:
Annotations
MeSH
Endosomes
Confidence
High
MeSH
Neurons
MeSH
Down Syndrome

a(CHEBI:"amyloid-beta") increases bp(HBP:HBP00061) View Subject | View Object

While Abeta is neurotoxic, studies suggest that sAPPalpha is neuroprotective, making the subcellular distribution of APP an important factor in neurodegeneration [42-44] PubMed:21214928

Appears in Networks:
Annotations
Confidence
Medium
MeSH
Neurons

a(CHEBI:"amyloid-beta") increases bp(HBP:HBP00027) View Subject | View Object

Multiple lines of evidence demonstrate that overproduction of Abeta results in a neurodegenerative cascade leading to synaptic dysfunction, formation of intraneuronal fibrillary tangles and eventually neuron loss in affected areas of the brain [6,142] PubMed:21214928

Appears in Networks:
Annotations
MeSH
Endosomes
Confidence
High
MeSH
Neurons

a(CHEBI:"amyloid-beta") decreases bp(GO:"regulation of synapse structure or activity") View Subject | View Object

Multiple lines of evidence demonstrate that overproduction of Abeta results in a neurodegenerative cascade leading to synaptic dysfunction, formation of intraneuronal fibrillary tangles and eventually neuron loss in affected areas of the brain [6,142] PubMed:21214928

Appears in Networks:
Annotations
MeSH
Endosomes
Confidence
High
MeSH
Neurons

a(CHEBI:"amyloid-beta") decreases bp(GO:"regulation of synapse structure or activity") View Subject | View Object

Although excessive Abeta causes synaptic dysfunction and synapse loss [142], low levels of Abeta increase hippocampal longterm potentiation and enhances memory, indicating a novel positive, modulatory role on neurotransmission and memory [158,159] PubMed:21214928

Appears in Networks:
Annotations
MeSH
Endosomes
Confidence
High
MeSH
Neurons
MeSH
Down Syndrome

a(CHEBI:"amyloid-beta") increases bp(GO:"neurofibrillary tangle assembly") View Subject | View Object

Multiple lines of evidence demonstrate that overproduction of Abeta results in a neurodegenerative cascade leading to synaptic dysfunction, formation of intraneuronal fibrillary tangles and eventually neuron loss in affected areas of the brain [6,142] PubMed:21214928

Appears in Networks:
Annotations
MeSH
Endosomes
Confidence
High
MeSH
Neurons

a(CHEBI:"amyloid-beta") increases bp(GO:"neuron death") View Subject | View Object

Multiple lines of evidence demonstrate that overproduction of Abeta results in a neurodegenerative cascade leading to synaptic dysfunction, formation of intraneuronal fibrillary tangles and eventually neuron loss in affected areas of the brain [6,142] PubMed:21214928

Appears in Networks:
Annotations
MeSH
Endosomes
Confidence
High
MeSH
Neurons

a(CHEBI:"amyloid-beta") association bp(GO:"MAPK cascade") View Subject | View Object

Intraneuronal Abeta can also impair amygdala-dependent emotional responses by affecting the ERK/MAPK signaling pathway [153] PubMed:21214928

Appears in Networks:
Annotations
MeSH
Endosomes
Confidence
High
MeSH
Neurons
MeSH
Down Syndrome

a(CHEBI:"amyloid-beta") association bp(GO:"ERK1 and ERK2 cascade") View Subject | View Object

Intraneuronal Abeta can also impair amygdala-dependent emotional responses by affecting the ERK/MAPK signaling pathway [153] PubMed:21214928

Appears in Networks:
Annotations
MeSH
Endosomes
Confidence
High
MeSH
Neurons
MeSH
Down Syndrome

a(CHEBI:"amyloid-beta") decreases a(MESH:Synapses) View Subject | View Object

Although excessive Abeta causes synaptic dysfunction and synapse loss [142], low levels of Abeta increase hippocampal longterm potentiation and enhances memory, indicating a novel positive, modulatory role on neurotransmission and memory [158,159] PubMed:21214928

Appears in Networks:
Annotations
MeSH
Endosomes
Confidence
High
MeSH
Neurons
MeSH
Down Syndrome

a(CHEBI:"amyloid-beta") decreases bp(GO:memory) View Subject | View Object

Although excessive Abeta causes synaptic dysfunction and synapse loss [142], low levels of Abeta increase hippocampal longterm potentiation and enhances memory, indicating a novel positive, modulatory role on neurotransmission and memory [158,159] PubMed:21214928

Appears in Networks:
Annotations
MeSH
Endosomes
Confidence
High
MeSH
Neurons
MeSH
Down Syndrome

a(CHEBI:"amyloid-beta") association bp(MESH:"Synaptic Transmission") View Subject | View Object

Although excessive Abeta causes synaptic dysfunction and synapse loss [142], low levels of Abeta increase hippocampal longterm potentiation and enhances memory, indicating a novel positive, modulatory role on neurotransmission and memory [158,159] PubMed:21214928

Appears in Networks:
Annotations
MeSH
Endosomes
Confidence
High
MeSH
Neurons
MeSH
Down Syndrome

a(CHEBI:"amyloid-beta") decreases bp(GO:"long-term synaptic potentiation") View Subject | View Object

Although excessive Abeta causes synaptic dysfunction and synapse loss [142], low levels of Abeta increase hippocampal longterm potentiation and enhances memory, indicating a novel positive, modulatory role on neurotransmission and memory [158,159] PubMed:21214928

Appears in Networks:
Annotations
MeSH
Endosomes
Confidence
High
MeSH
Hippocampus
MeSH
Down Syndrome

a(CHEBI:"amyloid-beta") association a(MESH:"Potassium Channels") View Subject | View Object

Picomolar levels of Abeta can also rescue neuronal cell death induced by inhibition of Abeta generation (by exposure to inhibitors of beta- or gamma-scretases) [160], possibly through regulating the potassium ion channel expression, hence affecting neuronal excitability [161] PubMed:21214928

Appears in Networks:
Annotations
MeSH
Endosomes
Confidence
Low
MeSH
Hippocampus
MeSH
Down Syndrome

a(CHEBI:"amyloid-beta") increases bp(GO:"cell death") View Subject | View Object

Picomolar levels of Abeta can also rescue neuronal cell death induced by inhibition of Abeta generation (by exposure to inhibitors of beta- or gamma-scretases) [160], possibly through regulating the potassium ion channel expression, hence affecting neuronal excitability [161] PubMed:21214928

Appears in Networks:
Annotations
MeSH
Endosomes
Confidence
Low
MeSH
Hippocampus
MeSH
Down Syndrome

a(CHEBI:"amyloid-beta") association complex(p(HGNC:APBA1), p(HGNC:APP)) View Subject | View Object

APP interaction with mint proteins has been shown to affect APP processing by stabilizing cellular APP, altering both sAPPalpha and Abeta generation and secretion [166] PubMed:21214928

Appears in Networks:
Annotations
MeSH
Endosomes
Confidence
High
MeSH
Hippocampus
MeSH
Down Syndrome

sec(a(CHEBI:"amyloid-beta")) association complex(p(HGNC:APBA1), p(HGNC:APP)) View Subject | View Object

APP interaction with mint proteins has been shown to affect APP processing by stabilizing cellular APP, altering both sAPPalpha and Abeta generation and secretion [166] PubMed:21214928

Appears in Networks:
Annotations
MeSH
Endosomes
Confidence
High
MeSH
Hippocampus
MeSH
Down Syndrome

a(CHEBI:"amyloid-beta") association complex(p(HGNC:APBA2), p(HGNC:APP)) View Subject | View Object

APP interaction with mint proteins has been shown to affect APP processing by stabilizing cellular APP, altering both sAPPalpha and Abeta generation and secretion [166] PubMed:21214928

Appears in Networks:
Annotations
MeSH
Endosomes
Confidence
High
MeSH
Hippocampus
MeSH
Down Syndrome

sec(a(CHEBI:"amyloid-beta")) association complex(p(HGNC:APBA2), p(HGNC:APP)) View Subject | View Object

APP interaction with mint proteins has been shown to affect APP processing by stabilizing cellular APP, altering both sAPPalpha and Abeta generation and secretion [166] PubMed:21214928

Appears in Networks:
Annotations
MeSH
Endosomes
Confidence
High
MeSH
Hippocampus
MeSH
Down Syndrome

a(CHEBI:"amyloid-beta") association complex(p(HGNC:APBA3), p(HGNC:APP)) View Subject | View Object

APP interaction with mint proteins has been shown to affect APP processing by stabilizing cellular APP, altering both sAPPalpha and Abeta generation and secretion [166] PubMed:21214928

Appears in Networks:
Annotations
MeSH
Endosomes
Confidence
High
MeSH
Hippocampus
MeSH
Down Syndrome

sec(a(CHEBI:"amyloid-beta")) association complex(p(HGNC:APBA3), p(HGNC:APP)) View Subject | View Object

APP interaction with mint proteins has been shown to affect APP processing by stabilizing cellular APP, altering both sAPPalpha and Abeta generation and secretion [166] PubMed:21214928

Appears in Networks:
Annotations
MeSH
Endosomes
Confidence
High
MeSH
Hippocampus
MeSH
Down Syndrome

a(CHEBI:"amyloid-beta") association a(CHEBI:"phorbol ester") View Subject | View Object

Indeed, phorbol ester’s effect on sAPPalpha secretion and Abeta generation though activation of protein kinase C (PKC) has been known for a long time [201-203] PubMed:21214928

Appears in Networks:
Annotations
MeSH
Cell Membrane
Confidence
High
MeSH
Hippocampus
MeSH
Down Syndrome

a(CHEBI:"amyloid-beta") decreases bp(GO:"regulation of synapse structure or activity") View Subject | View Object

Abeta toxicity can lead to synaptic dysfunction, neuronal cell death, impaired learning/memory and abnormal behaviors in AD models in vitro and in vivo PubMed:22122372

Appears in Networks:
Annotations
Confidence
High

a(CHEBI:"amyloid-beta") decreases bp(GO:"regulation of synapse structure or activity") View Subject | View Object

Studies have demonstrated that Abeta overproduction leads to neurotoxicity, neuronal tangle formation, synaptic damage and eventually neuron loss in the pathologically affected brain regions (Selkoe 1998; Shankar and Walsh 2009) PubMed:22122372

Appears in Networks:
Annotations
Confidence
High
MeSH
Neurons

a(CHEBI:"amyloid-beta") increases bp(GO:"neuron death") View Subject | View Object

Abeta toxicity can lead to synaptic dysfunction, neuronal cell death, impaired learning/memory and abnormal behaviors in AD models in vitro and in vivo PubMed:22122372

Appears in Networks:
Annotations
Confidence
High

a(CHEBI:"amyloid-beta") increases bp(GO:"neuron death") View Subject | View Object

Studies have demonstrated that Abeta overproduction leads to neurotoxicity, neuronal tangle formation, synaptic damage and eventually neuron loss in the pathologically affected brain regions (Selkoe 1998; Shankar and Walsh 2009) PubMed:22122372

Appears in Networks:
Annotations
Confidence
High
MeSH
Neurons

a(CHEBI:"amyloid-beta") decreases bp(GO:"learning or memory") View Subject | View Object

Abeta toxicity can lead to synaptic dysfunction, neuronal cell death, impaired learning/memory and abnormal behaviors in AD models in vitro and in vivo PubMed:22122372

Appears in Networks:
Annotations
Confidence
High

a(CHEBI:"amyloid-beta") increases a(HBP:HBP00038) View Subject | View Object

gamma-Secretase further cleaves C99 to release AICD and the amyloidogenic Abeta peptide which aggregates and fibrillates to form amyloid plaques in the brain PubMed:22122372

Appears in Networks:
Annotations
Confidence
Medium
MeSH
Neurons

a(CHEBI:"amyloid-beta") increases a(HBP:HBP00018) View Subject | View Object

gamma-Secretase further cleaves C99 to release AICD and the amyloidogenic Abeta peptide which aggregates and fibrillates to form amyloid plaques in the brain PubMed:22122372

Appears in Networks:
Annotations
Confidence
Medium
MeSH
Neurons

a(CHEBI:"amyloid-beta") increases bp(HBP:HBP00061) View Subject | View Object

Studies have demonstrated that Abeta overproduction leads to neurotoxicity, neuronal tangle formation, synaptic damage and eventually neuron loss in the pathologically affected brain regions (Selkoe 1998; Shankar and Walsh 2009) PubMed:22122372

Appears in Networks:
Annotations
Confidence
High
MeSH
Neurons

a(CHEBI:"amyloid-beta") increases bp(HBP:HBP00061) View Subject | View Object

Although excessive Abeta causes neurotoxicity, some studies have shown that Abeta 40 protects neurons against Abeta 42- induced neuronal damage and is required for the viability of central neurons (Plant et al. 2003; Zou et al. 2003) PubMed:22122372

Appears in Networks:
Annotations
Confidence
High
MeSH
Neurons

a(CHEBI:"amyloid-beta") increases bp(GO:"neurofibrillary tangle assembly") View Subject | View Object

Studies have demonstrated that Abeta overproduction leads to neurotoxicity, neuronal tangle formation, synaptic damage and eventually neuron loss in the pathologically affected brain regions (Selkoe 1998; Shankar and Walsh 2009) PubMed:22122372

Appears in Networks:
Annotations
Confidence
High
MeSH
Neurons

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

Appears in Networks:
Annotations
MeSH
Brain

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

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

Appears in Networks:

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

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

Appears in Networks:

a(CHEBI:"amyloid-beta") increases path(HBP:neurotoxicity) View Subject | View Object

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

Appears in Networks:
Annotations
MeSH
Brain

act(a(CHEBI:"amyloid-beta")) increases path(HBP:neurotoxicity) View Subject | View Object

In SHSY5Y cells, RNA interference (RNAi) knockdown of alpha7 enhanced Abeta toxicity (Qi et al., 2007), and alpha7 antagonists, but not alpha4beta2 antagonists, block galantamine protection of cultured rat neurons (Kihara et al., 2004). Donepezil protects cultured rat cortical neurons against Abeta toxicity through both alpha7 and non-alpha7 nAChRs (Takada et al., 2003). It is therefore likely that alpha7 nAChRs are the primary mediators of nicotine neuroprotection, but in some cells, non-alpha7 subtypes are also likely to contribute. PubMed:19293145

Appears in Networks:

act(a(CHEBI:"amyloid-beta")) increases path(HBP:neurotoxicity) View Subject | View Object

Genistein, a phytoestrogen, protects SH-SY5Y cells (Bang et al., 2004) as well as cultured hippocampal neurons (Zeng et al., 2004) from Abeta toxicity. However, in addition to its action on estrogen receptors, genistein is also a general tyrosine kinase inhibitor that protects cultured neurons from L-glutamate toxicity (Kajta et al., 2007). PubMed:19293145

Appears in Networks:
Annotations
Experimental Factor Ontology (EFO)
SH-SY5Y

act(a(CHEBI:"amyloid-beta")) increases path(HBP:neurotoxicity) View Subject | View Object

Thus, it seems that nAChRs may play a role in mediating Abeta toxicity through synergistic mechanisms; in addition to possible direct interactions (binding), nAChRs may also result in accelerated cell death through enhancing intracellular Abeta accumulation. PubMed:19293145

Appears in Networks:

a(CHEBI:"amyloid-beta") association bp(GO:"synaptic transmission, cholinergic") View Subject | View Object

There is abundant evidence that Abeta also affects cholinergic signaling in the brain. Recent studies indicate that brain nAChRs are not only affected by Abeta but can also initiate signaling pathways that protect against Abeta toxicity (Kihara et al., 1997b; Takada et al., 2003; Arias et al., 2005; Akaike, 2006; Meunier et al., 2006; Dineley, 2007; Liu et al., 2007). PubMed:19293145

Appears in Networks:
Annotations
MeSH
Brain

a(CHEBI:"amyloid-beta") association bp(GO:"synaptic transmission, cholinergic") View Subject | View Object

Consequently, there is mounting evidence that Abeta affects cholinergic signaling independent of its cytotoxic action. For example, Abeta blocks long-term potentiation, a cellular correlate of learning, through activation of JNK and p38MAPK (Wang et al., 2004). PubMed:19293145

Appears in Networks:

a(CHEBI:"amyloid-beta") association p(HGNCGENEFAMILY:"Cholinergic receptors nicotinic subunits") View Subject | View Object

There is abundant evidence that Abeta also affects cholinergic signaling in the brain. Recent studies indicate that brain nAChRs are not only affected by Abeta but can also initiate signaling pathways that protect against Abeta toxicity (Kihara et al., 1997b; Takada et al., 2003; Arias et al., 2005; Akaike, 2006; Meunier et al., 2006; Dineley, 2007; Liu et al., 2007). PubMed:19293145

Appears in Networks:
Annotations
MeSH
Brain

a(CHEBI:"amyloid-beta") association p(HGNCGENEFAMILY:"Cholinergic receptors nicotinic subunits") View Subject | View Object

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

Appears in Networks:

a(CHEBI:"amyloid-beta") association act(p(HGNCGENEFAMILY:"Cholinergic receptors nicotinic subunits")) View Subject | View Object

Although there is abundant evidence that Abeta can affect nAChR function, studies disagree as to whether Abeta is an antagonist or an agonist at nAChRs (these findings are summarized in Table 1). For example, Abeta has been reported to inhibit single-channel nicotinic receptor currents in rat hippocampal interneurons (Pettit et al., 2001) as well as currents recorded from human alpha7 receptors heterologously expressed in Xenopus laevis oocytes (Tozaki et al., 2002; Grassi et al., 2003; Pym et al., 2005). Abeta, however, activates a mutant (L250T) of the alpha7 receptor—this mutant conducts current in the desensitized state, indicating that Abeta may exert its antagonistic action through receptor desensitization (Grassi et al., 2003). PubMed:19293145

Appears in Networks:

a(CHEBI:"amyloid-beta") decreases p(HGNCGENEFAMILY:"Cholinergic receptors nicotinic subunits") View Subject | View Object

Similar effects of Abeta on nAChR expression have been confirmed in studies using cultured cells; Abeta causes a reduced expression of nAChRs in PC12 cells (Guan et al., 2001), and alpha4, alpha3, and alpha7 expression are all increased in cultured rat astrocytes (Xiu et al., 2005). PubMed:19293145

Appears in Networks:
Annotations
Experimental Factor Ontology (EFO)
PC12

a(CHEBI:"amyloid-beta") decreases act(p(HGNCGENEFAMILY:"Cholinergic receptors nicotinic subunits")) View Subject | View Object

Tg2576 mice expressing human Abeta show reduced [3H]cytisine binding (a label of nAChRs) in the cortex at 17 months after birth (Apelt et al., 2002). In contrast, however, levels of alpha7 or alpha4 subunits were unchanged in double-mutant Swedish APP/PS-1 mice as determined by radiolabeled cytosine (alpha4beta2) or alpha-bungarotoxin (alpha7) binding (Marutle et al., 2002). PubMed:19293145

Appears in Networks:
Annotations
MeSH
Cerebral Cortex

a(CHEBI:"amyloid-beta") positiveCorrelation p(HGNC:CHRNA7) View Subject | View Object

In addition, not only have alpha7 nAChRs been found colocalized with plaques (Wang et al., 2000b) but alpha7 and alpha4 subunits are also positively correlated with neurons that accumulate Abeta (Wevers et al., 1999). PubMed:19293145

Appears in Networks:
Annotations
MeSH
Neurons

a(CHEBI:"amyloid-beta") increases act(p(HGNC:CHRNA7)) View Subject | View Object

Curiously, although most studies are in agreement that nAChRs need to be activated to mediate their protective effects, mouse cortical neurons are protected by the alpha7 antagonist methyllycaconitine (Martin et al., 2004), raising the possibility that neuroprotection by alpha7 agonists may be through desensitization rather than activation of this rapidly desensitizing receptor. This would be consistent with the alpha7- dependent activation of intracellular signaling pathways by Abeta (Bell et al., 2004), but the opposite effects on cell survival exerted by Abeta and nicotine means that other mechanisms must be sought, such as ligand-specific coupling to downstream signaling pathways. PubMed:19293145

Appears in Networks:

a(CHEBI:"amyloid-beta") association p(HGNC:CHRNA7) View Subject | View Object

In contrast, Small et al. (2007) found no displacement of alpha-BTX from SH-SY5Y cells (a cell line very closely related to that used by Wang et al.) by either amyloid or methyllycaconitine. Wang et al. (2000b) also showed similar staining of human AD cortical neurons by alpha7 and Abeta antibodies in double immunofluorescence, suggesting that in human cortical neurons, alpha7 and Abeta are closely associated, although such an approach does not prove direct binding. However another study (Small et al., 2007) showed no displacement of labeled alpha-bungarotoxin from cell lines expressing rat alpha7 nAChRs. PubMed:19293145

Appears in Networks:
Annotations
Experimental Factor Ontology (EFO)
SH-SY5Y

a(CHEBI:"amyloid-beta") decreases act(p(HGNC:CHRNA7)) View Subject | View Object

Abeta action on nAChRs depends on subunit composition; it has been reported to block alpha7, transiently potentiate alpha4beta2 before blocking, and to have no action on alpha3beta4 (Pym et al., 2005). However, in contrast to its reported transient enhancement when expressed in oocytes, an inhibition of alpha4beta2 has been reported when expressed in human SH-EP1 cells (Wu et al., 2004). PubMed:19293145

Appears in Networks:

a(CHEBI:"amyloid-beta") causesNoChange p(HGNC:CHRNA7) View Subject | View Object

Again, despite numerous reports of a block of alpha7, one study indicated that Abeta failed to block alpha7, even though it blocked alpha4beta2, alpha2beta2 and alpha4alpha5beta2 receptors (Lamb et al., 2005). PubMed:19293145

Appears in Networks:

a(CHEBI:"amyloid-beta") causesNoChange act(p(HGNC:CHRNA7)) View Subject | View Object

It has also been observed that although Abeta inhibits recombinant human and mouse alpha7 nAChRs, transgenic mice overexpressing human Abeta express functional alpha7 nAChRs, and the amplitude of alpha7- mediated currents is no different from that of wild-type mice (Spencer et al., 2006). PubMed:19293145

Appears in Networks:

a(CHEBI:"amyloid-beta") increases p(HGNC:CHRNA7) View Subject | View Object

Similar effects of Abeta on nAChR expression have been confirmed in studies using cultured cells; Abeta causes a reduced expression of nAChRs in PC12 cells (Guan et al., 2001), and alpha4, alpha3, and alpha7 expression are all increased in cultured rat astrocytes (Xiu et al., 2005). PubMed:19293145

Appears in Networks:
Annotations
MeSH
Astrocytes

a(CHEBI:"amyloid-beta") positiveCorrelation p(HGNC:CHRNA4) View Subject | View Object

In addition, not only have alpha7 nAChRs been found colocalized with plaques (Wang et al., 2000b) but alpha7 and alpha4 subunits are also positively correlated with neurons that accumulate Abeta (Wevers et al., 1999). PubMed:19293145

Appears in Networks:
Annotations
MeSH
Neurons

a(CHEBI:"amyloid-beta") increases p(HGNC:CHRNA4) View Subject | View Object

Similar effects of Abeta on nAChR expression have been confirmed in studies using cultured cells; Abeta causes a reduced expression of nAChRs in PC12 cells (Guan et al., 2001), and alpha4, alpha3, and alpha7 expression are all increased in cultured rat astrocytes (Xiu et al., 2005). PubMed:19293145

Appears in Networks:
Annotations
MeSH
Astrocytes

a(CHEBI:"amyloid-beta") increases bp(GO:"intracellular receptor signaling pathway") View Subject | View Object

Curiously, although most studies are in agreement that nAChRs need to be activated to mediate their protective effects, mouse cortical neurons are protected by the alpha7 antagonist methyllycaconitine (Martin et al., 2004), raising the possibility that neuroprotection by alpha7 agonists may be through desensitization rather than activation of this rapidly desensitizing receptor. This would be consistent with the alpha7- dependent activation of intracellular signaling pathways by Abeta (Bell et al., 2004), but the opposite effects on cell survival exerted by Abeta and nicotine means that other mechanisms must be sought, such as ligand-specific coupling to downstream signaling pathways. PubMed:19293145

Appears in Networks:

act(a(CHEBI:"amyloid-beta")) association p(HGNC:FYN) View Subject | View Object

From these findings, it would seem that FYN plays a neuroprotective role. However, FYN may also play a paradoxical role in Abeta toxicity. Indeed, Abeta activates both FYN and the PI3K cascade (Williamson et al., 2002), whereas germline knockout of FYN is neuroprotective in mice (Lambert et al., 1998; Chin et al., 2004). FYN knockout protects mature mouse neurons in organotypic central nervous system cultures (Lambert et al., 1998). PubMed:19293145

Appears in Networks:

a(CHEBI:"amyloid-beta") increases act(p(HGNC:FYN)) View Subject | View Object

From these findings, it would seem that FYN plays a neuroprotective role. However, FYN may also play a paradoxical role in Abeta toxicity. Indeed, Abeta activates both FYN and the PI3K cascade (Williamson et al., 2002), whereas germline knockout of FYN is neuroprotective in mice (Lambert et al., 1998; Chin et al., 2004). FYN knockout protects mature mouse neurons in organotypic central nervous system cultures (Lambert et al., 1998). PubMed:19293145

Appears in Networks:

a(CHEBI:"amyloid-beta") increases act(p(FPLX:PI3K)) View Subject | View Object

From these findings, it would seem that FYN plays a neuroprotective role. However, FYN may also play a paradoxical role in Abeta toxicity. Indeed, Abeta activates both FYN and the PI3K cascade (Williamson et al., 2002), whereas germline knockout of FYN is neuroprotective in mice (Lambert et al., 1998; Chin et al., 2004). FYN knockout protects mature mouse neurons in organotypic central nervous system cultures (Lambert et al., 1998). PubMed:19293145

Appears in Networks:

a(CHEBI:"amyloid-beta") increases p(HGNC:MAPT, pmod(Ph, Tyr)) View Subject | View Object

FYN physically interacts with and phosphorylates tau protein, and the affinity of this physical interaction is enhanced in AD-associated mutations in tau protein (Bhaskar et al., 2005). Abeta rapidly induces tyrosine phosphorylation of many proteins (including tau protein) in human and cultured rat cortical neurons (Williamson et al., 2002). This phosphorylation is concomitant with phosphorylation and inactivation of focal adhesion kinase 1 (FADK1, a major downstream target of FYN), is blocked by inhibitors of SRC kinases and PI3K, and involves FYN associating physically with FADK1 (Williamson et al., 2002). PubMed:19293145

Appears in Networks:

act(a(CHEBI:"amyloid-beta")) association bp(GO:"calcium-mediated signaling") View Subject | View Object

Calcium signaling pathways are involved both in the toxic action of Abeta and in the protection against that toxicity offered by nicotinic ligands. Given that alpha7 homomeric nAChRs are much more permeable to calcium ions than are most other nAChRs (Bertrand et al., 1993), it is to be expected that nicotinic neuroprotection mediated by nAChRs, notably alpha7, would depend upon the activation of calcium signaling pathways. ABT-418 is a nicotinic agonist that protects primary rat cortical neurons from glutamate toxicity through its activation of alpha7 nAChRs, and this is blocked when calcium is removed from the extracellular medium (Donnelly-Roberts et al., 1996). PubMed:19293145

Appears in Networks:

a(CHEBI:"amyloid-beta") increases act(p(HGNC:MAPK8)) View Subject | View Object

Consequently, there is mounting evidence that Abeta affects cholinergic signaling independent of its cytotoxic action. For example, Abeta blocks long-term potentiation, a cellular correlate of learning, through activation of JNK and p38MAPK (Wang et al., 2004). PubMed:19293145

Appears in Networks:

a(CHEBI:"amyloid-beta") increases act(p(HGNC:MAPK14)) View Subject | View Object

Consequently, there is mounting evidence that Abeta affects cholinergic signaling independent of its cytotoxic action. For example, Abeta blocks long-term potentiation, a cellular correlate of learning, through activation of JNK and p38MAPK (Wang et al., 2004). PubMed:19293145

Appears in Networks:

a(CHEBI:"amyloid-beta") causesNoChange path(HBP:Neurodegeneration) View Subject | View Object

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

Appears in Networks:

a(CHEBI:"amyloid-beta") decreases a(MESH:Synapses) View Subject | View Object

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

Appears in Networks:

a(CHEBI:"amyloid-beta") decreases bp(MESH:"Neuronal Outgrowth") View Subject | View Object

For example, a recent study has shown that alpha7-specific ligands rescue the Abeta-induced decrease in neurite outgrowth of cultured mouse neurons (Hu et al., 2007). PubMed:19293145

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a(CHEBI:"amyloid-beta") decreases act(a(CHEBI:carbachol), ma(MESH:Hydrolysis)) View Subject | View Object

ApoE-epsilon4, but not ApoE-epsilon3, disrupts carbachol-stimulated phosphoinositol (PI) hydrolysis and so does Abeta and Abeta/ApoE-epsilon4 complexes in SH-SY5Y cells (Cedazo- Mínguez and Cowburn, 2001). The effect of Abeta and its ApoE complex on PI hydrolysis were blocked by estrogen, and this disruption was itself blocked by wortmannin, suggesting that PI3K mediates estrogen’s effect on PI hydrolysis. PubMed:19293145

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Annotations
Experimental Factor Ontology (EFO)
SH-SY5Y

a(CHEBI:"amyloid-beta") increases p(HGNC:MAPK1, pmod(Ph)) View Subject | View Object

Whatever the mechanism of uptake, it is interesting to note that the signaling pathways evoked by the accumulation of intracellular Abeta resemble those evoked by extracellularly applied Abeta: transgenic rats overexpressing Abeta intraneuronally display elevated levels of phosphorylated ERK2 (Echeverria et al., 2004), as do rat hippocampal slices in response to bath-applied Abeta (Dineley et al., 2001). Again, bath-applied Abeta causes an increase in BAX and a decrease in BCL2 expression in neurons or neuronlike cell lines (Koriyama et al., 2003; Clementi et al., 2006). PubMed:19293145

Appears in Networks:

a(CHEBI:"amyloid-beta") increases p(HGNC:BAX) View Subject | View Object

Whatever the mechanism of uptake, it is interesting to note that the signaling pathways evoked by the accumulation of intracellular Abeta resemble those evoked by extracellularly applied Abeta: transgenic rats overexpressing Abeta intraneuronally display elevated levels of phosphorylated ERK2 (Echeverria et al., 2004), as do rat hippocampal slices in response to bath-applied Abeta (Dineley et al., 2001). Again, bath-applied Abeta causes an increase in BAX and a decrease in BCL2 expression in neurons or neuronlike cell lines (Koriyama et al., 2003; Clementi et al., 2006). PubMed:19293145

Appears in Networks:

a(CHEBI:"amyloid-beta") increases act(p(HGNC:BAX)) View Subject | View Object

AKT interacts with BAD to regulate apoptosis and, interestingly, also has many interacting partners in the insulin signaling pathway. Abeta increased activity of BAD, lowered the activity of the antiapoptotic protein BCL2, in rat hippocampal neurons in primary culture (Koriyama et al., 2003) and has been shown to be toxic to human neuroblastoma cells by increasing BAX activity and decreasing BCl-2 activity (Clementi et al., 2006). PubMed:19293145

Appears in Networks:

a(CHEBI:"amyloid-beta") decreases p(HGNC:BCL2) View Subject | View Object

Whatever the mechanism of uptake, it is interesting to note that the signaling pathways evoked by the accumulation of intracellular Abeta resemble those evoked by extracellularly applied Abeta: transgenic rats overexpressing Abeta intraneuronally display elevated levels of phosphorylated ERK2 (Echeverria et al., 2004), as do rat hippocampal slices in response to bath-applied Abeta (Dineley et al., 2001). Again, bath-applied Abeta causes an increase in BAX and a decrease in BCL2 expression in neurons or neuronlike cell lines (Koriyama et al., 2003; Clementi et al., 2006). PubMed:19293145

Appears in Networks:

a(CHEBI:"amyloid-beta") decreases act(p(HGNC:BCL2)) View Subject | View Object

AKT interacts with BAD to regulate apoptosis and, interestingly, also has many interacting partners in the insulin signaling pathway. Abeta increased activity of BAD, lowered the activity of the antiapoptotic protein BCL2, in rat hippocampal neurons in primary culture (Koriyama et al., 2003) and has been shown to be toxic to human neuroblastoma cells by increasing BAX activity and decreasing BCl-2 activity (Clementi et al., 2006). PubMed:19293145

Appears in Networks:

act(a(CHEBI:"amyloid-beta")) increases bp(GO:"apoptotic process") View Subject | View Object

Thus, it seems that nAChRs may play a role in mediating Abeta toxicity through synergistic mechanisms; in addition to possible direct interactions (binding), nAChRs may also result in accelerated cell death through enhancing intracellular Abeta accumulation. PubMed:19293145

Appears in Networks:

a(CHEBI:"amyloid-beta") decreases act(a(CHEBI:nicotine)) View Subject | View Object

The most comprehensive study of the effects of Abeta at different concentrations showed that at 10 pM, Abeta evoked an inward current mediated by rat alpha7 nAChRs expressed in X. laevis oocytes, whereas at 100 nM, Abeta blocked nicotine responses through desensitization (Dineley et al., 2002). PubMed:19293145

Appears in Networks:

a(CHEBI:"amyloid-beta") increases p(HGNC:MAPT, pmod(Ph)) View Subject | View Object

It is also noteworthy that Abeta-induced tau protein phosphorylation in PC12 cells is inhibited not only by alpha7 agonists, as would be predicted from the role of alpha7 nAChRs in neuroprotection, but also by alpha-bungarotoxin (Hu et al., 2008), as might be predicted if the competition by alpha-bungarotoxin for the Abeta site blocked a direct action of Abeta on nAChRs. It is therefore possible that the toxicity of Abeta is mediated, at least in part, through a direct physical interaction between Abeta and nAChRs. PubMed:19293145

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Annotations
Experimental Factor Ontology (EFO)
PC12

a(CHEBI:"amyloid-beta") increases act(p(FPLX:JNK)) View Subject | View Object

In neuroblastoma cells, as well as cultured hippocampal neurons, Abeta activates JNK and ERK, and blocking these prevents Abeta hyperphosphorylating tau protein, as does alpha7 antisense oligonucleotides or alpha7 antagonists, suggesting that Abeta may trigger tau protein phosphorylation through ERK and JNK via alpha7 receptors (Wang et al., 2003b). Abeta leads to phosphorylation of AKT in cultured mouse neurons through a mechanism that requires alpha7 nAChRs (Abbott et al., 2008), AKT phosphorylation levels returning to baseline upon prolonged application of Abeta. PubMed:19293145

Appears in Networks:

a(CHEBI:"amyloid-beta") increases act(p(FPLX:ERK)) View Subject | View Object

In neuroblastoma cells, as well as cultured hippocampal neurons, Abeta activates JNK and ERK, and blocking these prevents Abeta hyperphosphorylating tau protein, as does alpha7 antisense oligonucleotides or alpha7 antagonists, suggesting that Abeta may trigger tau protein phosphorylation through ERK and JNK via alpha7 receptors (Wang et al., 2003b). Abeta leads to phosphorylation of AKT in cultured mouse neurons through a mechanism that requires alpha7 nAChRs (Abbott et al., 2008), AKT phosphorylation levels returning to baseline upon prolonged application of Abeta. PubMed:19293145

Appears in Networks:

a(CHEBI:"amyloid-beta") increases act(p(HGNC:BAD)) View Subject | View Object

AKT interacts with BAD to regulate apoptosis and, interestingly, also has many interacting partners in the insulin signaling pathway. Abeta increased activity of BAD, lowered the activity of the antiapoptotic protein BCL2, in rat hippocampal neurons in primary culture (Koriyama et al., 2003) and has been shown to be toxic to human neuroblastoma cells by increasing BAX activity and decreasing BCl-2 activity (Clementi et al., 2006). PubMed:19293145

Appears in Networks:

a(CHEBI:"amyloid-beta") association bp(GO:"choline transport") View Subject | View Object

For instance, in Abeta-overexpressing mice (PDAPP derived from a heterogeneous background comprising the strains C57BL/6J, DBA/2J, and Swiss-Webster), Abeta seems to target the high-affinity choline transporter (Bales et al., 2006). PubMed:19293145

Appears in Networks:

a(CHEBI:"amyloid-beta") increases act(p(HGNC:CHRNA7, var("p.L250T"))) View Subject | View Object

Although there is abundant evidence that Abeta can affect nAChR function, studies disagree as to whether Abeta is an antagonist or an agonist at nAChRs (these findings are summarized in Table 1). For example, Abeta has been reported to inhibit single-channel nicotinic receptor currents in rat hippocampal interneurons (Pettit et al., 2001) as well as currents recorded from human alpha7 receptors heterologously expressed in Xenopus laevis oocytes (Tozaki et al., 2002; Grassi et al., 2003; Pym et al., 2005). Abeta, however, activates a mutant (L250T) of the alpha7 receptor—this mutant conducts current in the desensitized state, indicating that Abeta may exert its antagonistic action through receptor desensitization (Grassi et al., 2003). PubMed:19293145

Appears in Networks:

a(CHEBI:"amyloid-beta") increases act(complex(p(HGNC:CHRNA4), p(HGNC:CHRNB2))) View Subject | View Object

Abeta action on nAChRs depends on subunit composition; it has been reported to block alpha7, transiently potentiate alpha4beta2 before blocking, and to have no action on alpha3beta4 (Pym et al., 2005). However, in contrast to its reported transient enhancement when expressed in oocytes, an inhibition of alpha4beta2 has been reported when expressed in human SH-EP1 cells (Wu et al., 2004). PubMed:19293145

Appears in Networks:

a(CHEBI:"amyloid-beta") decreases act(complex(p(HGNC:CHRNA4), p(HGNC:CHRNB2))) View Subject | View Object

Abeta action on nAChRs depends on subunit composition; it has been reported to block alpha7, transiently potentiate alpha4beta2 before blocking, and to have no action on alpha3beta4 (Pym et al., 2005). However, in contrast to its reported transient enhancement when expressed in oocytes, an inhibition of alpha4beta2 has been reported when expressed in human SH-EP1 cells (Wu et al., 2004). PubMed:19293145

Appears in Networks:

a(CHEBI:"amyloid-beta") decreases act(complex(p(HGNC:CHRNA4), p(HGNC:CHRNB2))) View Subject | View Object

Again, despite numerous reports of a block of alpha7, one study indicated that Abeta failed to block alpha7, even though it blocked alpha4beta2, alpha2beta2 and alpha4alpha5beta2 receptors (Lamb et al., 2005). PubMed:19293145

Appears in Networks:

a(CHEBI:"amyloid-beta") causesNoChange act(complex(p(HGNC:CHRNA3), p(HGNC:CHRNB4))) View Subject | View Object

Abeta action on nAChRs depends on subunit composition; it has been reported to block alpha7, transiently potentiate alpha4beta2 before blocking, and to have no action on alpha3beta4 (Pym et al., 2005). However, in contrast to its reported transient enhancement when expressed in oocytes, an inhibition of alpha4beta2 has been reported when expressed in human SH-EP1 cells (Wu et al., 2004). PubMed:19293145

Appears in Networks:

a(CHEBI:"amyloid-beta") decreases act(complex(p(HGNC:CHRNA2), p(HGNC:CHRNB2))) View Subject | View Object

Again, despite numerous reports of a block of alpha7, one study indicated that Abeta failed to block alpha7, even though it blocked alpha4beta2, alpha2beta2 and alpha4alpha5beta2 receptors (Lamb et al., 2005). PubMed:19293145

Appears in Networks:

a(CHEBI:"amyloid-beta") decreases act(complex(p(HGNC:CHRNA4), p(HGNC:CHRNA5), p(HGNC:CHRNB2))) View Subject | View Object

Again, despite numerous reports of a block of alpha7, one study indicated that Abeta failed to block alpha7, even though it blocked alpha4beta2, alpha2beta2 and alpha4alpha5beta2 receptors (Lamb et al., 2005). PubMed:19293145

Appears in Networks:

a(CHEBI:"amyloid-beta") decreases act(p(HGNC:CHRNA7, var("?"))) View Subject | View Object

It has also been observed that although Abeta inhibits recombinant human and mouse alpha7 nAChRs, transgenic mice overexpressing human Abeta express functional alpha7 nAChRs, and the amplitude of alpha7- mediated currents is no different from that of wild-type mice (Spencer et al., 2006). PubMed:19293145

Appears in Networks:

a(CHEBI:"amyloid-beta") increases p(HGNC:CHRNA3) View Subject | View Object

Similar effects of Abeta on nAChR expression have been confirmed in studies using cultured cells; Abeta causes a reduced expression of nAChRs in PC12 cells (Guan et al., 2001), and alpha4, alpha3, and alpha7 expression are all increased in cultured rat astrocytes (Xiu et al., 2005). PubMed:19293145

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Annotations
MeSH
Astrocytes

a(CHEBI:"amyloid-beta") decreases p(RGD:Chrna4) View Subject | View Object

Intracerebral injection of Abeta into rats resulted in a loss of alpha4 and alpha7 subunits as measured by Western blotting but an increase in alpha7 mRNA (Liu et al., 2008), again suggesting that Abeta directly reduces expression of alpha7 nAChRs through mechanisms other than reduced mRNAproduction, although caution should be exercised in interpreting quantitative data from Western blot studies. It is noteworthy that a combined patch-clamp and in situ hybridization study of dissociated human brain tissue (obtained as route-of-access tissue removed during surgery) indicated that neurons near Abeta plaques retained alpha4 and alpha7 mRNA transcripts, whereas these transcripts were absent in neurons burdened with hyperphosphorylated tau protein (Wevers et al., 1999). PubMed:19293145

Appears in Networks:

a(CHEBI:"amyloid-beta") decreases p(RGD:Chrna7) View Subject | View Object

Intracerebral injection of Abeta into rats resulted in a loss of alpha4 and alpha7 subunits as measured by Western blotting but an increase in alpha7 mRNA (Liu et al., 2008), again suggesting that Abeta directly reduces expression of alpha7 nAChRs through mechanisms other than reduced mRNAproduction, although caution should be exercised in interpreting quantitative data from Western blot studies. It is noteworthy that a combined patch-clamp and in situ hybridization study of dissociated human brain tissue (obtained as route-of-access tissue removed during surgery) indicated that neurons near Abeta plaques retained alpha4 and alpha7 mRNA transcripts, whereas these transcripts were absent in neurons burdened with hyperphosphorylated tau protein (Wevers et al., 1999). PubMed:19293145

Appears in Networks:

a(CHEBI:"amyloid-beta") increases r(RGD:Chrna7) View Subject | View Object

Intracerebral injection of Abeta into rats resulted in a loss of alpha4 and alpha7 subunits as measured by Western blotting but an increase in alpha7 mRNA (Liu et al., 2008), again suggesting that Abeta directly reduces expression of alpha7 nAChRs through mechanisms other than reduced mRNAproduction, although caution should be exercised in interpreting quantitative data from Western blot studies. It is noteworthy that a combined patch-clamp and in situ hybridization study of dissociated human brain tissue (obtained as route-of-access tissue removed during surgery) indicated that neurons near Abeta plaques retained alpha4 and alpha7 mRNA transcripts, whereas these transcripts were absent in neurons burdened with hyperphosphorylated tau protein (Wevers et al., 1999). PubMed:19293145

Appears in Networks:

a(CHEBI:"amyloid-beta") increases p(MGI:Chat) View Subject | View Object

In addition, APP or APP/PS-1 double-mutant mice have normal or even enhanced levels of ChAT and an unchanged cholinergic cell count (Hernandez et al., 2001). However, a double-mutant mouse expressing the Swedish APP and overexpressing human AChE showed enhanced mRNA levels of alpha7 in brain and adrenal medulla, although in brain tissue this enhancement declined with age. In this same mouse, there was no alteration in mRNA levels for alpha4, and an increase in alpha3 has also been observed in the brain and the adrenal medulla (Mousavi and Nordberg, 2006), a pattern similar to that seen in Abeta single-mutant mice (Bednar et al., 2002), suggesting that it is not attributable to the human AChE. PubMed:19293145

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Annotations
MeSH
Adrenal Medulla
MeSH
Brain

a(CHEBI:"amyloid-beta") increases r(MGI:Chrna3) View Subject | View Object

In addition, APP or APP/PS-1 double-mutant mice have normal or even enhanced levels of ChAT and an unchanged cholinergic cell count (Hernandez et al., 2001). However, a double-mutant mouse expressing the Swedish APP and overexpressing human AChE showed enhanced mRNA levels of alpha7 in brain and adrenal medulla, although in brain tissue this enhancement declined with age. In this same mouse, there was no alteration in mRNA levels for alpha4, and an increase in alpha3 has also been observed in the brain and the adrenal medulla (Mousavi and Nordberg, 2006), a pattern similar to that seen in Abeta single-mutant mice (Bednar et al., 2002), suggesting that it is not attributable to the human AChE. PubMed:19293145

Appears in Networks:
Annotations
MeSH
Adrenal Medulla
MeSH
Brain

a(CHEBI:"amyloid-beta") decreases a(CHEBI:acetylcholine) View Subject | View Object

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

Appears in Networks:
Annotations
MeSH
Alzheimer Disease

a(CHEBI:"amyloid-beta") decreases sec(a(CHEBI:acetylcholine)) View Subject | View Object

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

Appears in Networks:
Annotations
MeSH
Alzheimer Disease

a(CHEBI:"amyloid-beta") decreases act(p(FPLX:CHRM)) View Subject | View Object

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

Appears in Networks:
Annotations
MeSH
Alzheimer Disease

a(CHEBI:"amyloid-beta") positiveCorrelation p(HGNC:CHRNA7) View Subject | View Object

This prospect was supported by the finding that α7 nAChRs were found in plaques (159), and α7 and α4 subunits positively correlated with neurons that accumulated Aβ and hyperphosphorylated tau in AD brain tissue (161). PubMed:17009926

Appears in Networks:
Annotations
Cell Ontology (CL)
neuron
MeSH
Brain
MeSH
Alzheimer Disease

a(CHEBI:"amyloid-beta") positiveCorrelation p(HGNC:CHRNA4) View Subject | View Object

This prospect was supported by the finding that α7 nAChRs were found in plaques (159), and α7 and α4 subunits positively correlated with neurons that accumulated Aβ and hyperphosphorylated tau in AD brain tissue (161). PubMed:17009926

Appears in Networks:
Annotations
Cell Ontology (CL)
neuron
MeSH
Brain
MeSH
Alzheimer Disease

a(CHEBI:"amyloid-beta") increases a(HBP:"amyloid-beta fibrils") View Subject | View Object

In this work, kinetic analyses revealed that a structural motif in AChE (a hydrophobic sequence of 35 resides peptides) was able to promote amyloid formation and its incorporation into the growing Aβ-fibrils PubMed:26813123

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act(a(CHEBI:"amyloid-beta")) association act(p(HGNC:CHRM1)) View Subject | View Object

Interestingly, M1 receptor signaling affects several of AD major hallmarks, including cholinergic deficit, cognitive dysfunction, and tau and Aβ pathologies PubMed:26813123

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Annotations
MeSH
Alzheimer Disease

a(CHEBI:"amyloid-beta") regulates p(HGNC:MAPT, pmod(Ph)) View Subject | View Object

However, further studies have demonstrated that nicotinic receptor activation can lead to an increase in Aβ-mediated tau phosphorylation PubMed:26813123

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MeSH
Alzheimer Disease

a(CHEBI:"amyloid-beta") decreases complex(p(FPLX:"G_protein"), p(HGNC:CHRM1)) View Subject | View Object

In fact, Abeta has been shown to induce the uncoupling of M1 mAChR from G-protein, antagonizing the function of M1 mAChR under the pathological conditions of AD[96, 97]. Such an uncoupling may result in decreased signal transduction, reduced levels of sAPPalpha, and increased production of Abeta, triggering a vicious cycle. PubMed:24590577

Appears in Networks:
Annotations
MeSH
Alzheimer Disease

a(CHEBI:"amyloid-beta") decreases act(p(HGNC:CHRM1)) View Subject | View Object

In fact, Abeta has been shown to induce the uncoupling of M1 mAChR from G-protein, antagonizing the function of M1 mAChR under the pathological conditions of AD[96, 97]. Such an uncoupling may result in decreased signal transduction, reduced levels of sAPPalpha, and increased production of Abeta, triggering a vicious cycle. PubMed:24590577

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Annotations
MeSH
Alzheimer Disease

a(CHEBI:"amyloid-beta") increases path(HBP:neurotoxicity) View Subject | View Object

Nevertheless, a compound developed later, TBPB, selectively activates M1 mAChR in cell lines and shows no agonist activity in any other mAChR subtype. Interestingly, TBPB also potentiates the NMDA-evoked current in hippocampal pyramidal neurons, which is considered to be important for the effect of M1 mAChR on improving cognition. In addition, TBPB shifts the processing of APP in the non-amyloidogenic direction and thereafter decreases neurotoxic Abeta production vitro[120]. PubMed:24590577

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MeSH
Hippocampus
MeSH
Pyramidal Cells

a(CHEBI:"amyloid-beta") increases act(a(MESH:"alpha7 Nicotinic Acetylcholine Receptor")) View Subject | View Object

However, alpha7 nAChR activation was observed in X. laevis oocytes when a range of Abeta concentration spanning from 1 to 100 pM was applied (Dineley et al., 2002) PubMed:25514383

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a(CHEBI:"amyloid-beta") increases act(a(HBP:"beta-2-containing nAChR")) View Subject | View Object

Later it was shown that Abeta is able to activate also beta2*-nAChRs (beta2 subunit-containing nAChRs) PubMed:25514383

Appears in Networks:

act(a(CHEBI:"amyloid-beta")) negativeCorrelation a(HBP:"alpha-7 beta-2 nAChR") View Subject | View Object

This class of receptors seems to be particularly sensitive to Abeta-induced toxicity (Khiroug et al., 2002; Liu et al.,2009, 2012) PubMed:25514383

Appears in Networks:

a(CHEBI:"amyloid-beta") regulates act(p(FPLX:CHRN)) View Subject | View Object

Modulation of nAChRs by Abeta was also found in ex vivo studies: Pettit and colleagues (2001) used rat hippocampal slices to show that Abeta1-42 incubation is able to reduce postsynaptic currents and open probability of both alpha7 and non-alpha7 nAChRs subtypes, demonstrating an interaction between Abeta and other nAChR subunits PubMed:25514383

Appears in Networks:

a(CHEBI:"amyloid-beta") decreases act(p(FPLX:CHRN)) View Subject | View Object

It was then postulated that Abeta-nAChR interaction has a physiological role in neuronal homeostasis that is disrupted when Abeta concentrations increase in a pathological context, leading to receptor inhibition and possible cellular toxicity (Dineley et al., 2001; Parri et al., 2011) PubMed:25514383

Appears in Networks:

a(CHEBI:"amyloid-beta") increases act(a(CHEBI:acetylcholine)) View Subject | View Object

A different set of experiments demonstrated that Abeta enhances ACh activation of the alpha4beta2 nAChRs expressed in oocytes, this first activation of the receptor was followed by its inhibition (Pym et al., 2005) PubMed:25514383

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Cell Ontology (CL)
oocyte

a(CHEBI:"amyloid-beta") decreases act(a(MESH:"alpha7 Nicotinic Acetylcholine Receptor")) View Subject | View Object

In this system enhancement of Akt phosphorylation and activation of ERK pathway was observed following alpha7 agonist treatment, suggesting that Abeta inhibits the neuroprotective effect of alpha7 nAChR activation (Zhi et al., 2014) PubMed:25514383

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a(CHEBI:"amyloid-beta") increases bp(GO:memory) View Subject | View Object

An in vivo Abeta infusion in mice was able to enhance hippocampal dependent memory, highlighted with memory tasks such as the Morris water maze and contextual fear conditioning, which are both hippocampus dependent behavioural tasks (Puzzo et al.,2008) PubMed:25514383

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Annotations
MeSH
Hippocampus

a(CHEBI:"amyloid-beta") decreases bp(GO:"neuron cellular homeostasis") View Subject | View Object

It was then postulated that Abeta-nAChR interaction has a physiological role in neuronal homeostasis that is disrupted when Abeta concentrations increase in a pathological context, leading to receptor inhibition and possible cellular toxicity (Dineley et al., 2001; Parri et al., 2011) PubMed:25514383

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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

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Annotations
MeSH
Alzheimer Disease

a(CHEBI:"amyloid-beta") decreases a(GO:synapse) View Subject | View Object

The explanation proposed by the authors is that alpha7 nAChR activation through nicotine binding could promote survival pathways and recover the synaptic damage caused by Abeta (Inestrosa et al., 2013) PubMed:25514383

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Annotations
MeSH
Alzheimer Disease

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

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

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

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

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a(CHEBI:"amyloid-beta") decreases act(complex(GO:"proteasome complex")) View Subject | View Object

However, Abeta has been demonstrated to reduce proteasome activity in reticulocyte lysates (Gregori et al., 1995), suggesting that increased levels of the peptide could underlie the reduction in UPS function observed in the AD brain. PubMed:14556719

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MeSH
Reticulocytes

a(CHEBI:"amyloid-beta") decreases act(p(FPLX:Proteasome)) View Subject | View Object

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

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a(CHEBI:"amyloid-beta") increases p(HGNC:MAPT, frag("?", "17kD")) View Subject | View Object

Also, treating primary hippocampal neurons with pre-aggregated amyloid beta (Abeta) led to the generation of tau fragments of ∼35, ∼24, and ∼17 kDa, which was blocked by addition of a calpain inhibitor (52, 53). Tau fragments of the same size were also found in AD brain tissue (19). PubMed:24027553

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MeSH
Hippocampus
MeSH
Alzheimer Disease
Text Location
Review

a(CHEBI:"amyloid-beta") increases p(HGNC:MAPT, frag("?", "35kD")) View Subject | View Object

Also, treating primary hippocampal neurons with pre-aggregated amyloid beta (Abeta) led to the generation of tau fragments of ∼35, ∼24, and ∼17 kDa, which was blocked by addition of a calpain inhibitor (52, 53). Tau fragments of the same size were also found in AD brain tissue (19). PubMed:24027553

Appears in Networks:
Annotations
MeSH
Hippocampus
MeSH
Alzheimer Disease
Text Location
Review

a(CHEBI:"amyloid-beta") increases p(HGNC:MAPT, frag("?", "24kD")) View Subject | View Object

Also, treating primary hippocampal neurons with pre-aggregated amyloid beta (Abeta) led to the generation of tau fragments of ∼35, ∼24, and ∼17 kDa, which was blocked by addition of a calpain inhibitor (52, 53). Tau fragments of the same size were also found in AD brain tissue (19). PubMed:24027553

Appears in Networks:
Annotations
MeSH
Hippocampus
MeSH
Alzheimer Disease
Text Location
Review

a(CHEBI:"amyloid-beta") increases path(HBP:neurotoxicity) View Subject | View Object

Furthermore, recent evidence suggests that tau is essential for the neurotoxicity of amyloid-b, providing a possible link between these classic AD targets and suggesting that reductions in tau levels might be important via multiple, beneficial mechanisms [46–48] PubMed:21882945

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a(CHEBI:"amyloid-beta") causesNoChange p(MGI:Cdkn2a) View Subject | View Object

In 15-month-old mice with heavy Abeta deposition and phosphorylated tau, but lacking NFT pathology (Orr et al., 2014), Cdkn2a expression was not elevated (Figure 4e). These data indicate that Cdkn2a expression was neither a response to general protein accumulation, nor to pre-NFT tau pathology, but instead required the presence of NFTs PubMed:30126037

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Confidence
High
MeSH
Cerebral Cortex
MeSH
Hippocampus
MeSH
Alzheimer Disease

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

Meanwhile, an animal experiment showed that IDE expression will descend with age and diabetes, then resulting in Aβ deposition (Kochkina et al. 2015) PubMed:29626319

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a(CHEBI:"amyloid-beta") association a(MESH:Insulin) View Subject | View Object

In addition, insulin-degrading enzyme has been proposed to have a role in Aβ clearance through the BBB, which might explain why BBB clearance is sensitive to insulin.144 PubMed:26195256

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Annotations
MeSH
Hippocampus
MeSH
Temporal Lobe

a(CHEBI:"amyloid-beta") association bp(HBP:"perivascular drainage pathways") View Subject | View Object

Aβ is cleared along perivascular drainage pathways.83 In both AD44,160 and CAA44 (commonly associated with AD84), perivascular drainage of Aβ is impaired. PubMed:26195256

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MeSH
Hippocampus
MeSH
Temporal Lobe

a(CHEBI:"amyloid-beta") increases bp(GO:"response to oxidative stress") View Subject | View Object

The excessive deposition of Aβ also induces oxidative stress and mitochondrial dysfunction, which fails to offer ATP for the degradation of targeted proteins by UPS in yeast (Chen and Petranovic 2015) PubMed:29626319

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a(CHEBI:"amyloid-beta") increases bp(HBP:"mitochondrial dysfunction") View Subject | View Object

The excessive deposition of Aβ also induces oxidative stress and mitochondrial dysfunction, which fails to offer ATP for the degradation of targeted proteins by UPS in yeast (Chen and Petranovic 2015) PubMed:29626319

Appears in Networks:

a(CHEBI:"amyloid-beta") positiveCorrelation bp(GO:aging) View Subject | View Object

Meanwhile, an animal experiment showed that IDE expression will descend with age and diabetes, then resulting in Aβ deposition (Kochkina et al. 2015) PubMed:29626319

Appears in Networks:

a(CHEBI:"amyloid-beta") increases act(p(HGNC:MMP2)) View Subject | View Object

Among MMPs, MMP-2, -3 and -9, stimulated by Aβ, play important roles in degrading Aβ (Wang et al. 2014) PubMed:29626319

Appears in Networks:

a(CHEBI:"amyloid-beta") increases act(p(HGNC:MMP3)) View Subject | View Object

Among MMPs, MMP-2, -3 and -9, stimulated by Aβ, play important roles in degrading Aβ (Wang et al. 2014) PubMed:29626319

Appears in Networks:

a(CHEBI:"amyloid-beta") increases act(p(HGNC:MMP9)) View Subject | View Object

Among MMPs, MMP-2, -3 and -9, stimulated by Aβ, play important roles in degrading Aβ (Wang et al. 2014) PubMed:29626319

Appears in Networks:

tloc(a(CHEBI:"amyloid-beta"), fromLoc(MESH:Brain), toLoc(MESH:Blood)) decreases a(CHEBI:"amyloid-beta") View Subject | View Object

By collecting time-matched blood samples from cerebral vein, femoral vein, and radial artery in patients to measure the concentration of Aβ for every blood sample and figure out the turnover of it from vein to artery, it has been shown that transport of Aβ from brain to blood via the BBB and CSF absorption accounts for half of the total clearance of Aβ in CNS in humans, and furthermore, the clearance rate of Aβ via the BBB and CSF absorption accounts for the same proportion (Roberts et al. 2014) PubMed:29626319

Appears in Networks:

a(CHEBI:"amyloid-beta") decreases a(MESH:"Cerebrospinal Fluid") View Subject | View Object

In addition, Aβ deposition in CP also blocks CSF production in AD (Serot et al. 2012). PubMed:29626319

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Annotations
MeSH
Alzheimer Disease

deg(a(CHEBI:"amyloid-beta")) association p(HGNC:AQP4) View Subject | View Object

In addition, Jeffrey J. Iliff et al. have demonstrated that the Aβ in brain interstitium can be eliminated from the parenchyma by the bulk flow of interstitial fluid, which also depends on a water channel aquaporin-4 (AQP4) expressed in astrocyte endfeet PubMed:29626319

Appears in Networks:

a(CHEBI:"amyloid-beta") positiveCorrelation complex(p(HGNC:MAPT), p(INTERPRO:"Triosephosphate isomerase", pmod(NO))) View Subject | View Object

Taupositive material was present in the immunoprecipitates indicating that tau becomes associated to nitroTPI in an Ab dose-dependent pattern (Fig. 5A).TPI and nitro-TPI were incubated with tau protein and samples were analysed by Atomic Force Microscopy (Fig. 7A–D) and TEM (Fig. 7F and G). Abundant paired helical filament-like structures were found in samples containing nitro-TPI plus tau PubMed:19251756

Appears in Networks:

a(CHEBI:"amyloid-beta") increases bp(GO:"inflammatory response") View Subject | View Object

During Abeta-associated inflammation, reactive nitrogen and oxygen species are generated that can cause neuronal dysfunction and death (34-37). Prevalent among these species is peroxynitrite (ONOO-) PubMed:16566606

Appears in Networks:

a(CHEBI:"amyloid-beta") negativeCorrelation p(MGI:Dyrk1a) View Subject | View Object

Normalizing the gene dosage of Dyrk1A in the TS mouse rescued the density of senescent cells in the cingulate cortex, hippocampus and septum, prevented cholinergic neuron degeneration, and reduced App expression in the hippocampus, Aß load in the cortex and hippocampus, the expression of phosphorylated tau at the Ser202 residue in the hippocampus and cerebellum and the levels of total tau in the cortex, hippocampus and cerebellum. PubMed:29221819

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Annotations
Uberon
cerebral cortex
Uberon
hippocampal formation
MeSH
Alzheimer Disease
MeSH
Down Syndrome

a(CHEBI:"amyloid-beta") positiveCorrelation p(MGI:Syk) View Subject | View Object

We further validated Syk as a target-regulating Aβ by showing that pharmacological inhibition of Syk or down-regulation of Syk expression reduces Aβ production and increases the clearance of Aβ across the BBB mimicking (-)-nilvadipine effects. Moreover, treatment of transgenic mice overexpressing Aβ and transgenic Tau P301S mice with a selective Syk inhibitor respectively decreased brain Aβ accumulation and Tau hyperphosphorylation at multiple AD relevant epitopes. PubMed:25331948

Appears in Networks:

a(CHEBI:"amyloid-beta") negativeCorrelation m(MIRBASE:"rno-mir-195") View Subject | View Object

Chronic Brain hypoperfusion (CBH) elevates nuclear factor-kB (NF-kB), which binds with the promoter sequences of miR-195 and negatively regulates its expression. Down-regulated miR-195 up-regulates APP and BACE1 and increases Aß levels. Some Aß then enter the intracellular space and activate calpain, promoting the conversion of Cdk5/p35 to Cdk5/p25 and catalyzes the degradation of IkB (inhibitor of NF-?B)and directly phosphorylates Tau. Down-regulated miR-195 up-regulates p35, which provides the active substrates of p25 PubMed:26118667

Appears in Networks:

a(CHEBI:"amyloid-beta") increases p(INTERPRO:"Peptidase C2, calpain, catalytic domain") View Subject | View Object

Chronic Brain hypoperfusion (CBH) elevates nuclear factor-kB (NF-kB), which binds with the promoter sequences of miR-195 and negatively regulates its expression. Down-regulated miR-195 up-regulates APP and BACE1 and increases Aß levels. Some Aß then enter the intracellular space and activate calpain, promoting the conversion of Cdk5/p35 to Cdk5/p25 and catalyzes the degradation of IkB (inhibitor of NF-?B)and directly phosphorylates Tau. Down-regulated miR-195 up-regulates p35, which provides the active substrates of p25 PubMed:26118667

Appears in Networks:

a(CHEBI:"amyloid-beta") increases p(HGNC:MARK4) View Subject | View Object

Consistent with previous reports (11,34), treatment of rat hippocampal neurons with synthetic Aβ, prepared using a well-characterized procedure that enriches for Aβ oligomers (37), resulted in increased tau phosphorylation at the 12E8 sites (Fig. 2A), suggesting that Aβ treatment had activated MARK kinases. Increased phosphorylation of tau at a site recognized by the PHF-1 phospho-tau antibody was also observed (data not shown). PubMed:22156579

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Annotations
Uberon
hippocampal formation

a(CHEBI:"amyloid-beta") positiveCorrelation a(HBP:"Tau epitope, PHF1") View Subject | View Object

Consistent with previous reports (11,34), treatment of rat hippocampal neurons with synthetic Aβ, prepared using a well-characterized procedure that enriches for Aβ oligomers (37), resulted in increased tau phosphorylation at the 12E8 sites (Fig. 2A), suggesting that Aβ treatment had activated MARK kinases. Increased phosphorylation of tau at a site recognized by the PHF-1 phospho-tau antibody was also observed (data not shown). PubMed:22156579

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Annotations
Uberon
hippocampal formation

a(CHEBI:"amyloid-beta") positiveCorrelation p(MGI:Bace1) 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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act(a(CHEBI:"amyloid-beta")) negativeCorrelation composite(p(HGNC:MAPT, pmod(Ac, Lys, 163)), p(HGNC:MAPT, pmod(Ac, Lys, 280)), p(HGNC:MAPT, pmod(Ac, Lys, 281)), p(HGNC:MAPT, pmod(Ac, Lys, 369))) View Subject | View Object

We have used a knock-out/knock-in strategy in Drosophila to generate a strain with hTau inserted into the endogenous fly tau locus and expressed under the control of the endogenous fly tau promoter, thus avoiding potential toxicity due to genetic over-expression. hTau knock-in (KI) proteins were expressed at normal, endogenous levels, bound to fly microtubules and were post-translationally modified, hence displaying physiological properties. We used this new model to investigate the effects of acetylation on hTau toxicity in vivo. The simultaneous pseudo-acetylation of hTau at lysines 163, 280, 281 and 369 drastically decreased hTau phosphorylation and significantly reduced its binding to microtubules in vivo. These molecular alterations were associated with ameliorated amyloid beta toxicity. Our results indicate acetylation of hTau on multiple sites regulates its biology and ameliorates amyloid beta toxicity in vivo. PubMed:28855586

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a(CHEBI:"amyloid-beta") increases p(RGD:Mapt, pmod(Sumo)) View Subject | View Object

Furthermore, the enhanced SUMO-immunoreactivity, costained with the hyperphosphorylated tau, is detected in cerebral cortex of the AD brains, and β-amyloid exposure of rat primary hippocampal neurons induces a dose-dependent SUMOylation of the hyperphosphorylated tau. Our findings suggest that tau SUMOylation reciprocally stimulates its phosphorylation and inhibits the ubiquitination-mediated tau degradation, which provides a new insight into the AD-like tau accumulation. PubMed:25378699

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Annotations
Uberon
hippocampal formation

a(CHEBI:"amyloid-beta") positiveCorrelation p(HBP:"Tau aggregates") View Subject | View Object

In the HEK cell biosensor assay, tau from AD cases with plaques enhanced tau aggregates compared to tau from cases without plaques. In APP/PS1 cross with rTg4510 mice (P301L mutant human tau), tau seeding activity was threefold increased over the rTg4510 strain, without change in tau production or extracellular release. PubMed:28500862

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a(CHEBI:"amyloid-beta") increases act(complex(GO:"NLRP3 inflammasome complex")) View Subject | View Object

NLRP3 inflammasome activation results from TLR ligation and concomitant uptake of Ab in models of AD PubMed:28019679

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Annotations
Confidence
High
NeuroMMSigDB
Amyloidogenic subgraph

a(CHEBI:"amyloid-beta") increases a(CHEBI:"nitric oxide") View Subject | View Object

NLRP3 inflammasome formation and subsequent activation of caspase-1 cleavage capacity was instrumental for Abeta-induced nitric oxide production and TNF-a release PubMed:28019679

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Annotations
Confidence
High
NeuroMMSigDB
Amyloidogenic subgraph
NeuroMMSigDB
Nitric oxide subgraph

a(CHEBI:"amyloid-beta") increases bp(GO:"innate immune response") View Subject | View Object

One of the canonical pathways of this innate immune response evoked by Abeta is the activation of the NOD-like receptor (NLR) family, pyrin domain containing 3 (NLRP3) inflammasome that became a focus of intense research PubMed:28019679

Appears in Networks:
Annotations
Confidence
High
NeuroMMSigDB
Amyloidogenic subgraph
NeuroMMSigDB
Innate immune system subgraph

a(CHEBI:"amyloid-beta") increases sec(p(HGNC:TNF)) View Subject | View Object

NLRP3 inflammasome formation and subsequent activation of caspase-1 cleavage capacity was instrumental for Abeta-induced nitric oxide production and TNF-a release PubMed:28019679

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Annotations
Confidence
High
NeuroMMSigDB
Amyloidogenic subgraph
NeuroMMSigDB
Tumor necrosis factor subgraph

a(CHEBI:"amyloid-beta") increases act(complex(GO:"NLRP1 inflammasome complex")) View Subject | View Object

Further data, showing “neuronal pyroptosis” of Abeta exposed neurons in a NLRP1- dependent and caspase-1-mediated manner may point to a vicious cycle, by which NLRP1 is causing neurodegeneration in response to increased Abeta production (14) PubMed:28019679

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Annotations
Confidence
High
MeSH
Neurons
NeuroMMSigDB
Amyloidogenic subgraph

a(CHEBI:"amyloid-beta") increases act(p(HGNC:CASP1)) View Subject | View Object

Further data, showing “neuronal pyroptosis” of Abeta exposed neurons in a NLRP1- dependent and caspase-1-mediated manner may point to a vicious cycle, by which NLRP1 is causing neurodegeneration in response to increased Abeta production (14) PubMed:28019679

Appears in Networks:
Annotations
Confidence
Medium
MeSH
Neurons
NeuroMMSigDB
Apoptosis signaling subgraph
NeuroMMSigDB
Caspase subgraph

a(CHEBI:"amyloid-beta") increases act(p(HGNC:NLRP3)) View Subject | View Object

A few molecules, such as amyloid-β, can induce both NLRP3 priming through TLR activation and NLRP3 inflammasome activation68. PubMed:23702978

Appears in Networks:
Annotations
Confidence
High
NeuroMMSigDB
Caspase subgraph

a(CHEBI:"amyloid-beta") increases act(p(FPLX:TLR)) View Subject | View Object

A few molecules, such as amyloid-β, can induce both NLRP3 priming through TLR activation and NLRP3 inflammasome activation68. PubMed:23702978

Appears in Networks:
Annotations
Confidence
High
NeuroMMSigDB
Caspase subgraph

a(CHEBI:"amyloid-beta") increases act(complex(GO:"NLRP3 inflammasome complex")) View Subject | View Object

A few molecules, such as amyloid-β, can induce both NLRP3 priming through TLR activation and NLRP3 inflammasome activation68. PubMed:23702978

Appears in Networks:
Annotations
Confidence
High
NeuroMMSigDB
Caspase subgraph

a(CHEBI:"amyloid-beta") increases act(complex(GO:"inflammasome complex")) View Subject | View Object

Activators include bacteria, virus, fungus, protoza, microbial proteins, crystalline urea, RNA, Alum, ATP, potassium efflux, fatty acids, Aβ, and most recently, degraded mitochondrial DNA (Liu et al., 2013a; Mathew et al., 2012; Schmidt and Lenz, 2012) PubMed:24561250

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Annotations
Confidence
High
NeuroMMSigDB
Amyloidogenic subgraph

a(CHEBI:"amyloid-beta") increases bp(GO:phagocytosis) View Subject | View Object

Phagocytosis and subsequent lysosomal damage trigger by Aβ initiate the activation of the NLRP3 inflammasome in the microglia (Halle et al., 2008) PubMed:24561250

Appears in Networks:
Annotations
Cell Ontology (CL)
microglial cell
Confidence
High
NeuroMMSigDB
Amyloidogenic subgraph

a(CHEBI:"amyloid-beta") decreases a(GO:lysosome) View Subject | View Object

Phagocytosis and subsequent lysosomal damage trigger by Aβ initiate the activation of the NLRP3 inflammasome in the microglia (Halle et al., 2008) PubMed:24561250

Appears in Networks:
Annotations
Cell Ontology (CL)
microglial cell
Confidence
High
NeuroMMSigDB
Amyloidogenic subgraph
NeuroMMSigDB
Endosomal lysosomal subgraph

a(CHEBI:"amyloid-beta") association p(HGNC:NLRP3) View Subject | View Object

In AD, microglial cells and astrocytes express NLRP3, which in turn can detect A beta plaques and act by secreting caspase-1 to activate IL-1 beta and IL- 18 [23–25]. PubMed:27314526

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Annotations
Confidence
Medium
MeSH
Alzheimer Disease
NeuroMMSigDB
Amyloidogenic subgraph
NeuroMMSigDB
Caspase subgraph
NeuroMMSigDB
Interleukin signaling subgraph

a(CHEBI:"amyloid-beta") increases bp(GO:locomotion) View Subject | View Object

Transgenic mouse models of AD overexpressing Aβ peptides generally show greater locomotor activity and disinhibition in the elevated plus maze compared to non-transgenic mice, suggest- ing hyperactivity and a lower level of anxiety [28–30]. PubMed:26010758

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Annotations
MeSH
Alzheimer Disease

a(CHEBI:"amyloid-beta") decreases path(MESH:Anxiety) View Subject | View Object

Transgenic mouse models of AD overexpressing Aβ peptides generally show greater locomotor activity and disinhibition in the elevated plus maze compared to non-transgenic mice, suggest- ing hyperactivity and a lower level of anxiety [28–30]. PubMed:26010758

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Annotations
MeSH
Alzheimer Disease

a(CHEBI:"amyloid-beta") decreases path(MESH:"Interpersonal Relations") View Subject | View Object

Unlike wild-type mice, Tg PS1/APPswe mice elicited social interaction deficits and spent an equal amount of time in the chamber containing the empty cage or the chamber containing the unfamiliar (Stranger 1) mouse (Fig 4A). Anatabine at a dosage of 20mg/Kg/Day restored sociability in Tg PS1/APPswe mice as Tg PS1/APPswe mice treated with anatabine spent significantly more time in the chamber containing the unfamiliar mouse (Stranger 1) and less time in the chamber containing the empty cage (Fig 4B). PubMed:26010758

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MeSH
Alzheimer Disease

a(CHEBI:"amyloid-beta") increases p(HGNC:AIF1) View Subject | View Object

A significant increase in Iba-1 bur- den was observed in the cortex and hippocampus of Tg PS1/APPswe mice compared to their control wild-type littermates, suggesting increased Iba-1 immunopositive microglia in the brain of Tg PS1/APPswe mice (Fig 5A). PubMed:26010758

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Annotations
MeSH
Cerebral Cortex
MeSH
Hippocampus
MeSH
Alzheimer Disease

a(CHEBI:"amyloid-beta") increases p(HGNC:PTPRC) View Subject | View Object

A significant increase in CD45 immunopositive microglia/macrophage was observed in the cortex of Tg PS1/APPswe mice compared to wild- type mice (CD45 immunonegative) (Fig 5C). PubMed:26010758

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Annotations
Cell Ontology (CL)
macrophage
Cell Ontology (CL)
microglial cell
MeSH
Cerebral Cortex
MeSH
Alzheimer Disease

a(CHEBI:"amyloid-beta") increases p(HGNC:STAT3, pmod(Ph)) View Subject | View Object

We ob- served an elevation of STAT3 phosphorylation in the hippocampus and cortex of Tg PS1/ APPswe compared to their control wild-type littermates (Fig 6A). PubMed:26010758

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Annotations
MeSH
Cerebral Cortex
MeSH
Hippocampus
MeSH
Alzheimer Disease

a(CHEBI:"amyloid-beta") increases act(p(FPLX:NFkappaB)) View Subject | View Object

We also observed elevation of NFκB activation in the vicinity of Aβ deposits in the brain of Tg PS1/APPswe mice (Fig 7A). PubMed:26010758

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Annotations
MeSH
Brain
MeSH
Alzheimer Disease

a(CHEBI:"amyloid-beta") increases r(HGNC:BACE1) View Subject | View Object

Additionally, we found that Bace1 mRNA expression is significantly increased in the brain of Tg PS1/APPswe mice compared to wild- type littermates, whereas a significant reduction in Bace1 mRNA levels is observed in Tg PS1/ APPswe receiving 20 mg/Kg/Day of anatabine in their drinking water showing that at this dosage anatabine can mitigate the upregulation of Bace1 expression in Tg PS1/APPswe mice (Fig 9). PubMed:26010758

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Annotations
MeSH
Brain
MeSH
Alzheimer Disease

a(CHEBI:"amyloid-beta") association bp(GO:"axonal transport") View Subject | View Object

The amount of Aβ produced could be altered by delayed axonal transport, as well as the precise species of metabolites of APPproduced— e.g., Aβ40 or 42, monomeric Aβ, or Aβ-oligomers or Aβ-derived diffusible ligands (ADDLs) (Lambert et al., 1998; Walsh et al., 2000). PubMed:12428809

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a(CHEBI:"amyloid-beta") positiveCorrelation p(HGNC:PICALM) View Subject | View Object

Overexpression of PICALM in APP/PS1 mice substantially elevates Aβ levels, whereas knockdown reduces the Aβ plaque load, respectively [98] PubMed:29758300

Appears in Networks:

a(CHEBI:"amyloid-beta") positiveCorrelation act(complex(GO:"TOR complex")) View Subject | View Object

For instance, while accumulation of Aβ activates the mTOR signaling pathway and subsequently blocks macroautophagy, rapamycin reduces the Aβ load by enhancing macroautophagy [32] PubMed:29758300

Appears in Networks:

a(CHEBI:"amyloid-beta") negativeCorrelation bp(GO:macroautophagy) View Subject | View Object

For instance, while accumulation of Aβ activates the mTOR signaling pathway and subsequently blocks macroautophagy, rapamycin reduces the Aβ load by enhancing macroautophagy [32] PubMed:29758300

Appears in Networks:

sec(a(CHEBI:"amyloid-beta")) decreases path(HBP:Neurodegeneration) View Subject | View Object

This inhibition of Aβ secretion during macroautophagy deficiency results in aberrant cytosolic accumulation of Aβ, which ultimately evokes neurodegeneration accompanied with memory loss. PubMed:29758300

Appears in Networks:

sec(a(CHEBI:"amyloid-beta")) increases bp(GO:memory) View Subject | View Object

This inhibition of Aβ secretion during macroautophagy deficiency results in aberrant cytosolic accumulation of Aβ, which ultimately evokes neurodegeneration accompanied with memory loss. PubMed:29758300

Appears in Networks:

a(CHEBI:"amyloid-beta") increases p(HGNC:TARDBP, pmod(Ph)) View Subject | View Object

Although exact relations remain unknown, it was reported that Aβ can induce a cascade that results in phosphorylation and subsequent deposition of TDP-43 in the cytosol [70] PubMed:29758300

Appears in Networks:

a(CHEBI:"amyloid-beta") increases p(HGNC:TARDBP) View Subject | View Object

Although exact relations remain unknown, it was reported that Aβ can induce a cascade that results in phosphorylation and subsequent deposition of TDP-43 in the cytosol [70] PubMed:29758300

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MeSH
Cytosol

a(CHEBI:"amyloid-beta") negativeCorrelation p(HGNC:SORL1) View Subject | View Object

Identified as a candidate susceptibility gene for AD by GWAS [116], reduced level of SORL1 has been consistently correlated with brain Aβ levels [118,119]. PubMed:29758300

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a(CHEBI:"amyloid-beta") decreases act(a(GO:synapse)) View Subject | View Object

Moreover, administration of UCH-L1 can reverse the amyloid b-protein–induced synaptic dysfunction and memory loss in transgenic mice overexpressing APP and PS1 (Gong et al. 2006). PubMed:22908190

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a(CHEBI:"amyloid-beta") decreases bp(GO:memory) View Subject | View Object

Moreover, administration of UCH-L1 can reverse the amyloid b-protein–induced synaptic dysfunction and memory loss in transgenic mice overexpressing APP and PS1 (Gong et al. 2006). PubMed:22908190

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a(CHEBI:"amyloid-beta") negativeCorrelation act(complex(GO:"proteasome complex")) View Subject | View Object

Thus, the accumulation of tau and of Ab, forming the two major protein lesions of AD, impairs proteasome activity in vivo. PubMed:22908190

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Annotations
MeSH
Alzheimer Disease

a(CHEBI:"amyloid-beta") positiveCorrelation bp(GO:endocytosis) View Subject | View Object

Endocytic pathway up-regulation in AD stemming in part from pathological rab 5 activation generates higher levels of Ab (Mathews et al. 2002; Grbovic et al. 2003) that must be cleared in part by lysosomes. PubMed:22908190

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a(CHEBI:"amyloid-beta") positiveCorrelation bp(GO:endocytosis) View Subject | View Object

Pathological rab5 activation, which in Down syndrome is dependent on bCTF generation (Jiang et al. 2010), can up-regulate endocytosis in a manner functionally equivalent to the elevated endocytosis associated with increased synaptic activity, which is considered a source of Ab generation (Cirrito et al. 2008). PubMed:22908190

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MeSH
Down Syndrome

a(CHEBI:"amyloid-beta") positiveCorrelation a(CHEBI:"amyloid-beta polypeptide 42") View Subject | View Object

Consistent with these findings, strong overexpression of human Ab42, but not Ab40, in Drosophila neurons induces age-related accumulation of Ab in autolysosomes and neurotoxicity (Ling et al. 2009). PubMed:22908190

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Annotations
MeSH
Neurons

a(CHEBI:"amyloid-beta") association deg(p(HGNC:APP)) View Subject | View Object

Recent evidence suggests that the autophagic turnover of amyloid beta precursor protein (APP) may underlie the generation of toxic amyloid-β species [61]. PubMed:18930136

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a(CHEBI:"amyloid-beta") increases path(HBP:Excitotoxicity) View Subject | View Object

The interaction of tau with FYN may regulate the postsynaptic targeting of FYN, and thereby mediate Aβ‑induced excitotoxicity PubMed:26631930

Appears in Networks:

a(CHEBI:"amyloid-beta") increases path(HBP:Excitotoxicity) View Subject | View Object

Genetic deficiency of tau protects against excitotoxicity caused by Aβ or other excitotoxins in mice that overexpress human amyloid precursor protein (APP), in mice that express human APP and human presenilin 1 (PS1), and in mice that express mutant Scn1a (the gene encoding the voltage-gated sodium channel subunit Nav1.1), as well as in mice lacking the voltage-gated potassium channel Kv1.1 subunit PubMed:26631930

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a(CHEBI:"amyloid-beta") decreases bp(GO:"calcium ion homeostasis") View Subject | View Object

Amyloid-β induced apoptosis has also been ascribed to dyshomeostasis of intracellular Ca2+ and oxidative stress [106-108], two critical biochemical derangements known to activate NF-κB PubMed:28745240

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Annotations
MeSH
Alzheimer Disease

a(CHEBI:"amyloid-beta") association bp(MESH:"Oxidative Stress") View Subject | View Object

Amyloid-β induced apoptosis has also been ascribed to dyshomeostasis of intracellular Ca2+ and oxidative stress [106-108], two critical biochemical derangements known to activate NF-κB PubMed:28745240

Appears in Networks:
Annotations
MeSH
Alzheimer Disease

a(CHEBI:"amyloid-beta") increases bp(MESH:"Oxidative Stress") View Subject | View Object

In primary neuronal cultures, Amyloid-β has been shown to elicit oxidative stress and evoke NF-κB activation PubMed:28745240

Appears in Networks:
Annotations
MeSH
Alzheimer Disease

a(CHEBI:"amyloid-beta") increases bp(GO:"apoptotic process") View Subject | View Object

Amyloid-β has also been demonstrated to induce apoptosis via the JNK1/c-Jun/Fas ligand signaling cascade [110], which results in NF-κB activation PubMed:28745240

Appears in Networks:
Annotations
MeSH
Alzheimer Disease

a(CHEBI:"amyloid-beta") increases bp(GO:"apoptotic process") View Subject | View Object

Recent evidence has cogently shown that Amyloid-β induces apoptosis in rat primary neurons and human post-mitotic neuronal cells by reducing Bcl-XL expression level and evoking the release of cytochrome c from the mitochondria in a NF-κB – dependent manner PubMed:28745240

Appears in Networks:
Annotations
MeSH
Alzheimer Disease

a(CHEBI:"amyloid-beta") increases bp(GO:"JNK cascade") View Subject | View Object

Amyloid-β has also been demonstrated to induce apoptosis via the JNK1/c-Jun/Fas ligand signaling cascade [110], which results in NF-κB activation PubMed:28745240

Appears in Networks:
Annotations
MeSH
Alzheimer Disease

a(CHEBI:"amyloid-beta") increases bp(GO:"Fas signaling pathway") View Subject | View Object

Amyloid-β has also been demonstrated to induce apoptosis via the JNK1/c-Jun/Fas ligand signaling cascade [110], which results in NF-κB activation PubMed:28745240

Appears in Networks:
Annotations
MeSH
Alzheimer Disease

a(CHEBI:"amyloid-beta") increases act(complex(GO:"NF-kappaB complex")) View Subject | View Object

Recent evidence has cogently shown that Amyloid-β induces apoptosis in rat primary neurons and human post-mitotic neuronal cells by reducing Bcl-XL expression level and evoking the release of cytochrome c from the mitochondria in a NF-κB – dependent manner PubMed:28745240

Appears in Networks:
Annotations
MeSH
Alzheimer Disease

a(CHEBI:"amyloid-beta") increases act(complex(GO:"NF-kappaB complex")) View Subject | View Object

Furthermore, fibrillar Amyloid-β has been shown to activate NF-κB via the assembly pf the C5b-MAC complex PubMed:28745240

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Annotations
MeSH
Alzheimer Disease

a(CHEBI:"amyloid-beta") increases complex(GO:"NF-kappaB complex") View Subject | View Object

Furthermore, Amyloid-β actuates NF-κB – dependent pro-inflammatory pathways in microglia culminating in TNFα expression and subsequently TNFα effectuated neurotoxicity PubMed:28745240

Appears in Networks:
Annotations
MeSH
Alzheimer Disease

a(CHEBI:"amyloid-beta") increases act(complex(GO:"NF-kappaB complex")) View Subject | View Object

In primary neuronal cultures, Amyloid-β has been shown to elicit oxidative stress and evoke NF-κB activation PubMed:28745240

Appears in Networks:
Annotations
MeSH
Alzheimer Disease

a(CHEBI:"amyloid-beta") increases act(complex(GO:"NF-kappaB complex")) View Subject | View Object

Furthermore, Amyloid-β –induced NF-κB also results in the up-regulation of the antioxidant mitochondrial membrane enzyme – MnSOD (superoxide dismutase 2) [328] which is well known to combat oxidative stress and apoptosis PubMed:28745240

Appears in Networks:
Annotations
MeSH
Alzheimer Disease

a(CHEBI:"amyloid-beta") decreases p(HGNC:BCL2L1) View Subject | View Object

Recent evidence has cogently shown that Amyloid-β induces apoptosis in rat primary neurons and human post-mitotic neuronal cells by reducing Bcl-XL expression level and evoking the release of cytochrome c from the mitochondria in a NF-κB – dependent manner PubMed:28745240

Appears in Networks:
Annotations
MeSH
Alzheimer Disease

a(CHEBI:"amyloid-beta") decreases sec(a(PUBCHEM:16057918)) View Subject | View Object

Recent evidence has cogently shown that Amyloid-β induces apoptosis in rat primary neurons and human post-mitotic neuronal cells by reducing Bcl-XL expression level and evoking the release of cytochrome c from the mitochondria in a NF-κB – dependent manner PubMed:28745240

Appears in Networks:
Annotations
MeSH
Mitochondria
MeSH
Alzheimer Disease

a(CHEBI:"amyloid-beta") increases complex(a(GO:"membrane attack complex"), p(HGNC:C5)) View Subject | View Object

Furthermore, fibrillar Amyloid-β has been shown to activate NF-κB via the assembly pf the C5b-MAC complex PubMed:28745240

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MeSH
Alzheimer Disease

a(CHEBI:"amyloid-beta") increases p(HGNC:TNF) View Subject | View Object

Furthermore, Amyloid-β actuates NF-κB – dependent pro-inflammatory pathways in microglia culminating in TNFα expression and subsequently TNFα effectuated neurotoxicity PubMed:28745240

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MeSH
Alzheimer Disease

a(CHEBI:"amyloid-beta") increases p(HGNC:APP) View Subject | View Object

Indeed, Checler and colleagues have shown in a recent study that, NF-κB mediates the Amyloid-β – induced increase in expression of AβPP in HEK293 cells PubMed:28745240

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Experimental Factor Ontology (EFO)
HEK293
MeSH
Alzheimer Disease

a(CHEBI:"amyloid-beta") increases act(complex(GO:"calcium- and calmodulin-dependent protein kinase complex")) View Subject | View Object

There is evidence that Amyloid-β causes the activation of Ca2+/calmodulin/CamKII pathway [332-334], thereby potentially leading to NF-κB activation. PubMed:28745240

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MeSH
Alzheimer Disease

a(CHEBI:"amyloid-beta") regulates act(p(FPLX:PKC)) View Subject | View Object

Moreover, there is preponderance of data implicating Amyloid-β in the modulation of PKC signaling pathway [335-338] and the PI3K/Akt/mTOR signaling pathway [339-341], which are known to activate NF-κB signaling pathway PubMed:28745240

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MeSH
Alzheimer Disease

a(CHEBI:"amyloid-beta") regulates bp(HBP:"PI3K-Akt signaling pathway") View Subject | View Object

Moreover, there is preponderance of data implicating Amyloid-β in the modulation of PKC signaling pathway [335-338] and the PI3K/Akt/mTOR signaling pathway [339-341], which are known to activate NF-κB signaling pathway PubMed:28745240

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MeSH
Alzheimer Disease

a(CHEBI:"amyloid-beta") increases path(HBP:neurotoxicity) View Subject | View Object

Furthermore, negative regulators of NF-κB such as the NAD+- dependent histone deacetylase – SIRT1, abolish the deleterious neurotoxic effects of Amyloid-β PubMed:28745240

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MeSH
Alzheimer Disease

a(CHEBI:"amyloid-beta") increases a(CHEBI:"calcium(2+)") View Subject | View Object

Emerging evidence has implicated Amyloid-β in augmenting cytosolic Ca2+ levels and causing NF- κB activation via calcineurin in astrocytes PubMed:28745240

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MeSH
Cytosol
MeSH
Alzheimer Disease

a(CHEBI:"amyloid-beta") increases act(a(MESH:Microglia)) View Subject | View Object

Amyloid-β also induces microglial activation that results in NF-κB – induced expression of pro-inflammatory cytokines such as TNFα, IL1β, IL6, and IL8 from the microglia resulting in neuronal death PubMed:28745240

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MeSH
Alzheimer Disease

a(CHEBI:"amyloid-beta") increases bp(GO:"glial cell activation") View Subject | View Object

Glial activation, pro-inflammatory gene expression and elevated secretion of IL-1, IL-6 and TNF- are consequences of high A levels [30,31]. PubMed:29179999

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a(CHEBI:"amyloid-beta") increases bp(GO:"inflammatory response") View Subject | View Object

Glial activation, pro-inflammatory gene expression and elevated secretion of IL-1, IL-6 and TNF- are consequences of high A levels [30,31]. PubMed:29179999

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a(CHEBI:"amyloid-beta") increases sec(p(HGNC:IL1B)) View Subject | View Object

Glial activation, pro-inflammatory gene expression and elevated secretion of IL-1, IL-6 and TNF- are consequences of high A levels [30,31]. PubMed:29179999

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a(CHEBI:"amyloid-beta") increases sec(p(HGNC:IL6)) View Subject | View Object

Glial activation, pro-inflammatory gene expression and elevated secretion of IL-1, IL-6 and TNF- are consequences of high A levels [30,31]. PubMed:29179999

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a(CHEBI:"amyloid-beta") increases sec(p(HGNC:TNF)) View Subject | View Object

Glial activation, pro-inflammatory gene expression and elevated secretion of IL-1, IL-6 and TNF- are consequences of high A levels [30,31]. PubMed:29179999

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a(CHEBI:"amyloid-beta") increases act(p(FPLX:NFkappaB)) View Subject | View Object

Furthermore, A induced NF-B activity in glial and neuronal cells. NF-B is involved in inflammatory responses and is expressed in brains of AD patients [32]. PubMed:29179999

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Cell Ontology (CL)
glial cell

a(CHEBI:"amyloid-beta") increases act(p(FPLX:NFkappaB)) View Subject | View Object

In cell models triggering supraphysiological concentrations of Aβ pep- tides, NF-κB is activated, as well as in both neuronal cells and microglial cells, showing that NF-κB pathway has been linked to Aβ neurotoxicity [14]. PubMed:27288790

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MeSH
Microglia
MeSH
Neurons

a(CHEBI:"amyloid-beta") increases act(p(HGNC:NFKB1)) View Subject | View Object

Further investigations confirm that the activation of p50 and RelA subunit contributes to the apoptotic program in cells exposed to the Aβ [17]. PubMed:27288790

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a(CHEBI:"amyloid-beta") increases act(p(HGNC:RELA)) View Subject | View Object

Further investigations confirm that the activation of p50 and RelA subunit contributes to the apoptotic program in cells exposed to the Aβ [17]. PubMed:27288790

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a(CHEBI:"amyloid-beta") increases act(complex(GO:"NF-kappaB complex")) View Subject | View Object

Under physiological conditions activation of NF-κB by endogenous Aβ reduces βAPP, BACE1 and the γ-secretase activity, thereby lowering Aβ processing and facilitating Aβ homeostasis PubMed:25652642

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a(CHEBI:"amyloid-beta") positiveCorrelation act(complex(GO:"NF-kappaB complex")) View Subject | View Object

However in AD, exposure to high Aβ concentrations upregulates NF-κB activation increasing βAPP and Aβ processing, precipitating a feed-back loop that favor exacerbated Aβ production PubMed:25652642

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MeSH
Alzheimer Disease

a(CHEBI:"amyloid-beta") decreases act(complex(GO:"NF-kappaB complex")) View Subject | View Object

Mechanistically, the Aβ induced neuronal apoptosis has been attributed to the increase in the ratio of proapoptotic gene (BAX) transcription to that of the anti-apoptotic gene Bcl-Xl, and/or to the reduction in constitutively activated NF-κB with consequent increase in the cytoplasmic IκB proteins PubMed:25652642

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MeSH
Alzheimer Disease

a(CHEBI:"amyloid-beta") increases act(complex(GO:"NF-kappaB complex")) View Subject | View Object

This is supported by the observation that in mixed neuronal-glial cell cultures, Aβ induces increasing degree of neurotoxicity in an NF-κB dependent manner in the presence of higher proportion of glial cells PubMed:25652642

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MeSH
Neuroglia
MeSH
Neurons
MeSH
Alzheimer Disease

a(CHEBI:"amyloid-beta") increases act(p(HGNC:APOE)) View Subject | View Object

Aβ has been shown to upregulate APOE in astroglial cells. This upregulation was inhibited by decoy-κB nucleotides supporting a critical role for NFκB in APOE function PubMed:25652642

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MeSH
Astrocytes
MeSH
Alzheimer Disease

a(CHEBI:"amyloid-beta") increases bp(GO:"neuron death") View Subject | View Object

Mechanistically, the Aβ induced neuronal apoptosis has been attributed to the increase in the ratio of proapoptotic gene (BAX) transcription to that of the anti-apoptotic gene Bcl-Xl, and/or to the reduction in constitutively activated NF-κB with consequent increase in the cytoplasmic IκB proteins PubMed:25652642

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MeSH
Alzheimer Disease

a(CHEBI:"amyloid-beta") increases p(HGNC:BAX) View Subject | View Object

Mechanistically, the Aβ induced neuronal apoptosis has been attributed to the increase in the ratio of proapoptotic gene (BAX) transcription to that of the anti-apoptotic gene Bcl-Xl, and/or to the reduction in constitutively activated NF-κB with consequent increase in the cytoplasmic IκB proteins PubMed:25652642

Appears in Networks:
Annotations
MeSH
Alzheimer Disease

a(CHEBI:"amyloid-beta") decreases p(HGNC:BCL2L1) View Subject | View Object

Mechanistically, the Aβ induced neuronal apoptosis has been attributed to the increase in the ratio of proapoptotic gene (BAX) transcription to that of the anti-apoptotic gene Bcl-Xl, and/or to the reduction in constitutively activated NF-κB with consequent increase in the cytoplasmic IκB proteins PubMed:25652642

Appears in Networks:
Annotations
MeSH
Alzheimer Disease

a(CHEBI:"amyloid-beta") increases a(MESH:"I-kappa B Proteins") View Subject | View Object

Mechanistically, the Aβ induced neuronal apoptosis has been attributed to the increase in the ratio of proapoptotic gene (BAX) transcription to that of the anti-apoptotic gene Bcl-Xl, and/or to the reduction in constitutively activated NF-κB with consequent increase in the cytoplasmic IκB proteins PubMed:25652642

Appears in Networks:
Annotations
MeSH
Alzheimer Disease

a(CHEBI:"amyloid-beta") increases path(HBP:neurotoxicity) View Subject | View Object

This is supported by the observation that in mixed neuronal-glial cell cultures, Aβ induces increasing degree of neurotoxicity in an NF-κB dependent manner in the presence of higher proportion of glial cells PubMed:25652642

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Annotations
MeSH
Neuroglia
MeSH
Neurons
MeSH
Alzheimer Disease

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

In addition, most DLB patients show most features of AD (i.e., hyperphosphorylated tau deposits and A beta) to various extents PubMed:30061532

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About

BEL Commons is developed and maintained in an academic capacity by Charles Tapley Hoyt and Daniel Domingo-Fernández at the Fraunhofer SCAI Department of Bioinformatics with support from the IMI project, AETIONOMY. It is built on top of PyBEL, an open source project. Please feel free to contact us here to give us feedback or report any issues. Also, see our Publishing Notes and Data Protection information.

If you find BEL Commons useful in your work, please consider citing: Hoyt, C. T., Domingo-Fernández, D., & Hofmann-Apitius, M. (2018). BEL Commons: an environment for exploration and analysis of networks encoded in Biological Expression Language. Database, 2018(3), 1–11.