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PubMed: 18986241

Title
Cholinergic system during the progression of Alzheimer's disease: therapeutic implications.
Journal
Expert review of neurotherapeutics
Volume
8
Issue
None
Pages
1703-18
Date
2008-11-01
Authors
Mufson EJ | Ginsberg SD | Counts SE | Perez SE

Evidence 9e279885f5
JSON

A recent functional MRI study demonstrated that people with MCI treated with the FDA-approved anticholinesterase donepezil demonstrated increased frontal cortex activation relative to untreated controls, which was positively correlated with task performance [31].

a(CHEBI:donepezil) increases act(a(MESH:D005625)) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Cognitive Dysfunction

a(MESH:D005625) positiveCorrelation path(MESH:D011597) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Cognitive Dysfunction

path(MESH:D011597) positiveCorrelation a(MESH:D005625) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Cognitive Dysfunction

Evidence 60dbe8ec96
JSON

Notably, reports that physostigmine and oral anticholinesterases have beneficial effects for patients with AD suggest that the CBF system is somewhat preserved during the progression of dementia, despite well-documented loss of cholinergic biosynthetic machinery (including ChAT and AChE enzyme deficits) in patients with this disease. Interestingly, recent studies have shown that ChAT activity, which results in acetylcholine (ACh) synthesis, is preserved in the neocortex of people with MCI [18,19].

a(CHEBI:physostigmine) decreases path(MESH:D000544) View Subject | View Object

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

a(MESH:D002800) decreases path(MESH:D000544) View Subject | View Object

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

a(MESH:D059329) association path(MESH:D003704) View Subject | View Object

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

act(p(HGNC:CHAT)) directlyIncreases a(CHEBI:acetylcholine) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Neocortex
MeSH
Cognitive Dysfunction

path(MESH:D003704) association a(MESH:D059329) View Subject | View Object

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

path(MESH:D060825) causesNoChange act(p(HGNC:CHAT)) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Neocortex
MeSH
Cognitive Dysfunction

Evidence 22bc8bb73d
JSON

CBF neurons displaying the tau C3 epitope, a marker for early stage NFT formation, were often hyperinnervated by GAL-containing fibers, whereas CBF neurons displaying the tau epitope MN423, an end-stage NFT marker, were not associated with GAL. Single cell gene expression studies have demonstrated that the levels of mRNAs encoding select subclasses of PP1 subunits (e.g., PP1alpha and PP1gamma) are stable in GAL hyperinnervated but downregulated in non-hyperinnervated CBF neurons in AD [149]

a(HBP:"Tau C3") biomarkerFor path(MESH:D059329) View Subject | View Object

Appears in Networks:
Annotations
Disease Ontology (DO)
Alzheimer's disease
MeSH
Cholinergic Neurons
MeSH
Cognitive Dysfunction

act(p(HGNC:GAL)) causesNoChange a(HBP:"Tau MN423") View Subject | View Object

Appears in Networks:
Annotations
Disease Ontology (DO)
Alzheimer's disease
MeSH
Cholinergic Neurons
MeSH
Cognitive Dysfunction

act(p(HGNC:GAL)) increases r(HGNC:PPP1CA) View Subject | View Object

Appears in Networks:
Annotations
Disease Ontology (DO)
Alzheimer's disease
MeSH
Cholinergic Neurons
MeSH
Cognitive Dysfunction

act(p(HGNC:GAL)) increases r(HGNC:PPP1CC) View Subject | View Object

Appears in Networks:
Annotations
Disease Ontology (DO)
Alzheimer's disease
MeSH
Cholinergic Neurons
MeSH
Cognitive Dysfunction

Evidence 7c7d43e029
JSON

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]

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

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

a(MESH:D002800) increases bp(MESH:D000066829) View Subject | View Object

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

a(MESH:D002800) association bp(GO:"GO:0050435") View Subject | View Object

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

bp(GO:"GO:0050435") association a(MESH:D002800) View Subject | View Object

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

Evidence b470cfebac
JSON

Since the cholinergic deficit is not an early defect in the progression of AD [18–20], the use of these drugs in the prodromal stages of AD should be continued. However, the limited effect of cholinesterase inhibitors for the treatment of cognitive decline in AD coupled with unwanted side effects such as diarrhea, nausea, insomnia, fatigue and loss of appetite indicates the need to move beyond this conventional drug treatment with somewhat circumscribed efficacy.

a(MESH:D002800) association path(MESH:D007319) View Subject | View Object

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

a(MESH:D002800) association path(MESH:D003967) View Subject | View Object

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

a(MESH:D002800) association path(MESH:D009325) View Subject | View Object

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

a(MESH:D002800) association path(MESH:D005221) View Subject | View Object

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

a(MESH:D002800) association path(MESH:D000855) View Subject | View Object

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

path(MESH:D000855) association a(MESH:D002800) View Subject | View Object

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

path(MESH:D003967) association a(MESH:D002800) View Subject | View Object

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

path(MESH:D005221) association a(MESH:D002800) View Subject | View Object

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

path(MESH:D007319) association a(MESH:D002800) View Subject | View Object

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

path(MESH:D009325) association a(MESH:D002800) View Subject | View Object

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

Evidence 5b4c0b6291
JSON

The regions of the forebrain that contain cholinobasal and septohippocampal CBF neurons also display various non-cholinergic neurons, including GABAergic interneurons that innervate cholinergic perikarya [11]. In addition, neuropeptides often co-localize with CBF neurons. For example, the inhibitory neuropeptide galanin (GAL) is found in septohippocampal and NB neurons in rodents, but not in higher apes or humans where GAL fibers innvervate CBF neurons. [15].

a(MESH:D009479) association a(MESH:D059329) View Subject | View Object

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Annotations
MeSH
Basal Forebrain

a(MESH:D059329) association a(MESH:D009479) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Basal Forebrain

a(MESH:D059329) association a(MESH:D059330) View Subject | View Object

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Annotations
MeSH
Basal Forebrain

a(MESH:D059329) association p(RGD:Gal) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Basal Forebrain

a(MESH:D059330) association a(MESH:D059329) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Basal Forebrain

p(RGD:Gal) association a(MESH:D059329) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Basal Forebrain

Evidence 29e5e2f1d6
JSON

Cholinergic basal forebrain (CBF) cortical projection neurons contain the pathological AD hallmark, neurofibrillary tangles (NFTs), and undergo chemical phenotypic alterations during the progression of AD, making them an excellent natural model for studying mechanisms of cell death, survival and treatment approaches both in vitro and in vivo, including relevant animal models of neurodegeneration as well as human postmortem clinical pathological tissue studies [14].

a(MESH:D016874) association a(MESH:D059329) View Subject | View Object

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

a(MESH:D016874) association path(MESH:D000544) View Subject | View Object

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

a(MESH:D059329) association a(MESH:D016874) View Subject | View Object

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

a(MESH:D059329) association path(MESH:D000544) View Subject | View Object

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

path(MESH:D000544) association a(MESH:D059329) View Subject | View Object

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

path(MESH:D000544) association a(MESH:D016874) View Subject | View Object

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

Evidence c2b136c4d4
JSON

Butyrylcholinesterase (BChE) is a serine hydrolase similar to AChE that is widely distributed throughout the CNS and also catalyzes the hydrolysis of ACh. BChE is localized to neurons and glia, and is associated with NFTs and senile plaques (SPs) in AD brain [32]. Interestingly, population-based genetic studies of AD have identified a point mutation that changes Ala539 to threonine in the K variant of BChE, which effectively reduces serum BChE concentrations, and may be associated with cognitive decline [33]. BChE activity also increases in AD brain whereas AChE activity remains unchanged or declines [34,35].

a(MESH:D016874) association p(HGNC:BCHE) View Subject | View Object

Appears in Networks:
Annotations
Disease Ontology (DO)
Alzheimer's disease
MeSH
Neuroglia
MeSH
Neurons
MeSH
Cognitive Dysfunction

act(p(HGNC:BCHE), ma(cat)) directlyIncreases deg(a(CHEBI:acetylcholine)) View Subject | View Object

Appears in Networks:
Annotations
Disease Ontology (DO)
Alzheimer's disease
MeSH
Neuroglia
MeSH
Neurons
MeSH
Cognitive Dysfunction

p(HGNC:BCHE) association a(MESH:D016874) View Subject | View Object

Appears in Networks:
Annotations
Disease Ontology (DO)
Alzheimer's disease
MeSH
Neuroglia
MeSH
Neurons
MeSH
Cognitive Dysfunction

p(HGNC:BCHE) association path(MESH:D058225) View Subject | View Object

Appears in Networks:
Annotations
Disease Ontology (DO)
Alzheimer's disease
MeSH
Neuroglia
MeSH
Neurons
MeSH
Cognitive Dysfunction

p(HGNC:BCHE) association path(MESH:D003071) View Subject | View Object

Appears in Networks:
Annotations
Disease Ontology (DO)
Alzheimer's disease
MeSH
Neuroglia
MeSH
Neurons
MeSH
Cognitive Dysfunction

p(HGNC:BCHE, var("p.Ala539Thr")) decreases p(HGNC:BCHE) View Subject | View Object

Appears in Networks:
Annotations
Disease Ontology (DO)
Alzheimer's disease
MeSH
Neuroglia
MeSH
Neurons
MeSH
Cognitive Dysfunction

path(MESH:D000544) causesNoChange act(p(HGNC:ACHE)) View Subject | View Object

Appears in Networks:
Annotations
Disease Ontology (DO)
Alzheimer's disease
MeSH
Neuroglia
MeSH
Neurons
MeSH
Cognitive Dysfunction

path(MESH:D000544) decreases act(p(HGNC:ACHE)) View Subject | View Object

Appears in Networks:
Annotations
Disease Ontology (DO)
Alzheimer's disease
MeSH
Neuroglia
MeSH
Neurons
MeSH
Cognitive Dysfunction

path(MESH:D000544) increases act(p(HGNC:BCHE)) View Subject | View Object

Appears in Networks:
Annotations
Disease Ontology (DO)
Alzheimer's disease
MeSH
Neuroglia
MeSH
Neurons
MeSH
Cognitive Dysfunction

path(MESH:D003071) association p(HGNC:BCHE) View Subject | View Object

Appears in Networks:
Annotations
Disease Ontology (DO)
Alzheimer's disease
MeSH
Neuroglia
MeSH
Neurons
MeSH
Cognitive Dysfunction

path(MESH:D058225) association p(HGNC:BCHE) View Subject | View Object

Appears in Networks:
Annotations
Disease Ontology (DO)
Alzheimer's disease
MeSH
Neuroglia
MeSH
Neurons
MeSH
Cognitive Dysfunction

Evidence e69a8a66fc
JSON

Cholinergic neurons within the nucleus basalis (NB) and the septal diagonal band complex provide the major source of cholinergic innervation to the cerebral cortex and hippocampus, respectively, and play a key role in memory and attentional function [11–13].

a(MESH:D059329) directlyIncreases bp(GO:"GO:0060384") View Subject | View Object

Appears in Networks:
Annotations
MeSH
Basal Nucleus of Meynert
MeSH
Cerebral Cortex
MeSH
Hippocampus

a(MESH:D059329) association path(MESH:D008568) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Basal Nucleus of Meynert
MeSH
Cerebral Cortex
MeSH
Hippocampus

a(MESH:D059329) association path(MESH:D001288) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Basal Nucleus of Meynert
MeSH
Cerebral Cortex
MeSH
Hippocampus

path(MESH:D001288) association a(MESH:D059329) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Basal Nucleus of Meynert
MeSH
Cerebral Cortex
MeSH
Hippocampus

path(MESH:D008568) association a(MESH:D059329) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Basal Nucleus of Meynert
MeSH
Cerebral Cortex
MeSH
Hippocampus

Evidence f54eadca50
JSON

Specifically, progressive phenotypic downregulation of markers within CBF neurons as well as frank CBF cell loss has been observed consistently, along with an associated reduction of choline acetyltransferase (ChAT) and acetylcholinesterase (AChE) activity within the cortex in AD [16]. Most researchers presumed that progressive disruption of cholinergic function underlies much of the short-term memory loss seen in AD

a(MESH:D059329) association path(MESH:D008570) View Subject | View Object

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path(MESH:D000544) decreases a(MESH:D059329) View Subject | View Object

Appears in Networks:

path(MESH:D000544) decreases p(HGNC:CHAT) View Subject | View Object

Appears in Networks:

path(MESH:D000544) decreases p(HGNC:ACHE) View Subject | View Object

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path(MESH:D008570) association a(MESH:D059329) View Subject | View Object

Appears in Networks:

Evidence 67dd3173c2
JSON

Recently, a novel group of M1 partial agonists was developed (AF102B, AF150(S) and AF267B-i) [129]. In a series of studies using the 3x transgenic-AD mice, which recapitulate the major pathologies of AD [130], chronic AF267B treatment rescued cognitive impairment and decreased Abeta42 and tau pathologies in the cortex and hippocampus. These changes were associated with M1 mAChR-mediated activation of the TNFalpha-converting enzyme ADAM17/TACE, decreased BACE1 steady state levels and inhibition of GSK3beta [130].

a(MESHC:"(S)-2-ethyl-8-methyl-1-thia-4,8-diazaspiro(4.5)decan-3-one") decreases path(MESH:D060825) View Subject | View Object

Appears in Networks:
Annotations
Disease Ontology (DO)
Alzheimer's disease
MeSH
Cerebral Cortex
MeSH
Hippocampus
MeSH
Cognitive Dysfunction

a(MESHC:"(S)-2-ethyl-8-methyl-1-thia-4,8-diazaspiro(4.5)decan-3-one") decreases path(MESH:D024801) View Subject | View Object

Appears in Networks:
Annotations
Disease Ontology (DO)
Alzheimer's disease
MeSH
Cerebral Cortex
MeSH
Hippocampus
MeSH
Cognitive Dysfunction

a(MESHC:"(S)-2-ethyl-8-methyl-1-thia-4,8-diazaspiro(4.5)decan-3-one") decreases a(CHEBI:"amyloid-beta polypeptide 42") View Subject | View Object

Appears in Networks:
Annotations
Disease Ontology (DO)
Alzheimer's disease
MeSH
Cerebral Cortex
MeSH
Hippocampus
MeSH
Cognitive Dysfunction

a(MESHC:"(S)-2-ethyl-8-methyl-1-thia-4,8-diazaspiro(4.5)decan-3-one") increases act(p(MGI:Chrm1)) View Subject | View Object

Appears in Networks:
Annotations
Disease Ontology (DO)
Alzheimer's disease
MeSH
Cerebral Cortex
MeSH
Hippocampus
MeSH
Cognitive Dysfunction

a(MESHC:"(S)-2-ethyl-8-methyl-1-thia-4,8-diazaspiro(4.5)decan-3-one") decreases p(MGI:Bace1) View Subject | View Object

Appears in Networks:
Annotations
Disease Ontology (DO)
Alzheimer's disease
MeSH
Cerebral Cortex
MeSH
Hippocampus
MeSH
Cognitive Dysfunction

a(MESHC:"(S)-2-ethyl-8-methyl-1-thia-4,8-diazaspiro(4.5)decan-3-one") decreases act(p(MGI:Gsk3b)) View Subject | View Object

Appears in Networks:
Annotations
Disease Ontology (DO)
Alzheimer's disease
MeSH
Cerebral Cortex
MeSH
Hippocampus
MeSH
Cognitive Dysfunction

act(p(MGI:Chrm1)) increases act(p(MGI:Adam17)) View Subject | View Object

Appears in Networks:
Annotations
Disease Ontology (DO)
Alzheimer's disease
MeSH
Cerebral Cortex
MeSH
Hippocampus
MeSH
Cognitive Dysfunction

Evidence 3d3e9cf066
JSON

Gambogic amide binds selectively to TrkA (but not TrkB or TrkC), phosphorylates TrkA tyrosine residues, and activates the Akt and MAPK TrkA-mediated NGF signaling pathways. Gambogic amide has been demonstrated to ameliorate excitotoxic damage and promote neurite outgrowth in PC12 cells [116], making this a potential lead compound for chemical modification and clinical trial assessment.

a(MESHC:"gambogic amide") decreases bp(HBP:Excitotoxicity) View Subject | View Object

Appears in Networks:
Annotations
Experimental Factor Ontology (EFO)
PC12
MeSH
Cognitive Dysfunction

a(MESHC:"gambogic amide") increases bp(GO:"GO:0031175") View Subject | View Object

Appears in Networks:
Annotations
Experimental Factor Ontology (EFO)
PC12
MeSH
Cognitive Dysfunction

complex(a(MESHC:"gambogic amide"), p(HGNC:NTRK1)) directlyIncreases p(HGNC:NTRK1, pmod(Ph)) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Cognitive Dysfunction

p(HGNC:NTRK1, pmod(Ph)) increases bp(GO:"GO:0043491") View Subject | View Object

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MeSH
Cognitive Dysfunction

p(HGNC:NTRK1, pmod(Ph)) increases bp(GO:"GO:0000165") View Subject | View Object

Appears in Networks:
Annotations
MeSH
Cognitive Dysfunction

Evidence a4d64fc4ec
JSON

Significantly, while we have shown that reduced TrkA levels in the cortex were positively associated with lower cognitive performance as assessed by Mini-Mental State Exam (MMSE) test scores [64], increased cortical proNGF levels were negatively correlated with MMSE performance [61].

a(MESHC:"pro-nerve growth factor, human") positiveCorrelation path(MESH:D003072) View Subject | View Object

Appears in Networks:
Annotations
Disease Ontology (DO)
Alzheimer's disease
MeSH
Cerebral Cortex
MeSH
Cognitive Dysfunction

p(HGNC:NTRK1) negativeCorrelation path(MESH:D003072) View Subject | View Object

Appears in Networks:
Annotations
Disease Ontology (DO)
Alzheimer's disease
MeSH
Cerebral Cortex
MeSH
Cognitive Dysfunction

path(MESH:D000544) decreases p(HGNC:NTRK1) View Subject | View Object

Appears in Networks:
Annotations
Disease Ontology (DO)
Alzheimer's disease
MeSH
Cerebral Cortex
MeSH
Cognitive Dysfunction

path(MESH:D003072) negativeCorrelation p(HGNC:NTRK1) View Subject | View Object

Appears in Networks:
Annotations
Disease Ontology (DO)
Alzheimer's disease
MeSH
Cerebral Cortex
MeSH
Cognitive Dysfunction

path(MESH:D003072) positiveCorrelation a(MESHC:"pro-nerve growth factor, human") View Subject | View Object

Appears in Networks:
Annotations
Disease Ontology (DO)
Alzheimer's disease
MeSH
Cerebral Cortex
MeSH
Cognitive Dysfunction

Evidence ed7fb2390e
JSON

Thus, the concomitant reduction of TrkA and accumulation of proNGF in the cortex may be an early pathobiological marker for the onset of AD (Figure 1A). In fact, significantly increased cerebrospinal fluid (CSF) levels of NGF are detectable in AD [65], demonstrating the potential utility of NGF as a diagnostic biomarker.

a(MESHC:"pro-nerve growth factor, human") biomarkerFor path(MESH:D000544) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Cognitive Dysfunction

p(HGNC:NTRK1) biomarkerFor path(MESH:D000544) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Cognitive Dysfunction

path(MESH:D000544) increases p(HGNC:NGF) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Cerebrospinal Fluid
MeSH
Cognitive Dysfunction

Evidence 4bcf9f9f00
JSON

Recently, the novel non-selective antihistamine dimebon (2,3,4,5-tetrahydro2,8-dimethyl-5–2[-6methyl 3-pyridnyl)ethyl]-1H-pyrido[4,3-b] indole) was shown to inhibit BChE and AChE, block the NMDA receptor signaling pathway, inhibit mitochondrial permeability and provide neuroprotective effects in models of AD [194].

a(MESHC:latrepirdine) decreases act(p(HGNC:BCHE)) View Subject | View Object

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

a(MESHC:latrepirdine) decreases act(p(HGNC:ACHE)) View Subject | View Object

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

a(MESHC:latrepirdine) decreases bp(GO:"GO:0098989") View Subject | View Object

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

a(MESHC:latrepirdine) decreases bp(GO:"GO:0046902") View Subject | View Object

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

a(MESHC:latrepirdine) increases bp(MESH:D000066829) View Subject | View Object

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

Evidence f0a933072d
JSON

For example, NGF signal transduction activates the MAPK pathway, which participates in a wide array of biologic functions, including cell survival, differentiation and apoptosis [82–84]. MAPK is a serine/ threonine protein kinase which becomes activated upon phosphorylation and affects a wide variety of transcription factors [85].

bp(GO:"GO:0000165") association bp(GO:"GO:0006915") View Subject | View Object

Appears in Networks:
Annotations
MeSH
Cognitive Dysfunction

bp(GO:"GO:0000165") association bp(GO:"GO:0030182") View Subject | View Object

Appears in Networks:
Annotations
MeSH
Cognitive Dysfunction

bp(GO:"GO:0006915") association bp(GO:"GO:0000165") View Subject | View Object

Appears in Networks:
Annotations
MeSH
Cognitive Dysfunction

bp(GO:"GO:0030182") association bp(GO:"GO:0000165") View Subject | View Object

Appears in Networks:
Annotations
MeSH
Cognitive Dysfunction

act(p(HGNC:NGF)) increases bp(GO:"GO:0000165") View Subject | View Object

Appears in Networks:
Annotations
MeSH
Cognitive Dysfunction

p(GFAM:"Mitogen-activated protein kinases", pmod(Ph)) increases act(p(GFAM:"Mitogen-activated protein kinases")) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Cognitive Dysfunction

Evidence 17ac7f321e
JSON

The classic MAPK cascade involves activation of the small GTPase Ras, and the kinases Raf and MEK [86,87]. Downstream consequences of MAPK activation include activation of the ribosomal S6 kinases (Rsk) and the MAPK-activated protein kinase 2 (MAPKAP2), which phosphorylates several transcription factors including Elk-1 and cAMP-regulated response element binding protein (CREB) [85]. The physiological significance of this elaborate NGF-induced network remains unclear, but the sustained activation of MAPK is linked to neurotrophin-mediated neurite outgrowth [88,89]

bp(GO:"GO:0000165") increases act(p(FPLX:RAS)) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Cognitive Dysfunction

bp(GO:"GO:0000165") increases act(p(FPLX:RAF)) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Cognitive Dysfunction

bp(GO:"GO:0000165") increases act(p(FPLX:MEK)) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Cognitive Dysfunction

bp(GO:"GO:0000165") increases act(p(FPLX:P90RSK)) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Cognitive Dysfunction

bp(GO:"GO:0000165") increases act(p(HGNC:MAPKAPK2)) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Cognitive Dysfunction

bp(GO:"GO:0031175") association act(p(GFAM:"Mitogen-activated protein kinases")) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Cognitive Dysfunction

act(p(GFAM:"Mitogen-activated protein kinases")) association bp(GO:"GO:0031175") View Subject | View Object

Appears in Networks:
Annotations
MeSH
Cognitive Dysfunction

act(p(HGNC:MAPKAPK2)) increases p(HGNC:ELK1, pmod(Ph)) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Cognitive Dysfunction

act(p(HGNC:MAPKAPK2)) increases p(HGNC:CREB1, pmod(Ph)) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Cognitive Dysfunction

Evidence 8dde11cf15
JSON

Recent evidence supports the notion that p75NTR has an intrinsic signaling capacity including: • Sphingolipid metabolism [98–100] • Activation of the JNK pathway [52,54,56,101–103] • Activation of the NF-kappaB pathway [104–109] • Activation of the Akt pathway [110] • Activation of the MAPK pathway [97,111]

bp(GO:"GO:0006665") association act(p(HGNC:NGFR)) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Cognitive Dysfunction

act(p(HGNC:NGFR)) association bp(GO:"GO:0006665") View Subject | View Object

Appears in Networks:
Annotations
MeSH
Cognitive Dysfunction

act(p(HGNC:NGFR)) increases bp(GO:"GO:0007254") View Subject | View Object

Appears in Networks:
Annotations
MeSH
Cognitive Dysfunction

act(p(HGNC:NGFR)) increases bp(GO:"GO:0038061") View Subject | View Object

Appears in Networks:
Annotations
MeSH
Cognitive Dysfunction

act(p(HGNC:NGFR)) increases bp(GO:"GO:0043491") View Subject | View Object

Appears in Networks:
Annotations
MeSH
Cognitive Dysfunction

act(p(HGNC:NGFR)) increases bp(GO:"GO:0000165") View Subject | View Object

Appears in Networks:
Annotations
MeSH
Cognitive Dysfunction

Evidence 87e8374558
JSON

Single cell gene array studies have shown that synaptic transcripts are selectively downregulated in CBF neurons in AD, with significant reductions in synaptophysin and synaptotagmin but not synaptobrevin or SNAP29 mRNA [134,135]. Intriguingly, synaptotagmin function is related to vesicle-presynaptic membrane fusion and neurotransmitter release, suggesting that perturbations in presynaptic vesicle trafficking comprise a common event in vulnerable neuronal populations in AD. In contrast to synaptic transcripts, mRNAs encoding APP and Notch were unchanged between control and AD subjects, whereas acid hydrolase cathepsin D mRNA was upregulated in AD [134–136].

bp(GO:"GO:0007269") association p(GFAM:Synaptotagmins) View Subject | View Object

Appears in Networks:
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MeSH
Cognitive Dysfunction

bp(GO:"GO:0031629") association p(GFAM:Synaptotagmins) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Cognitive Dysfunction

p(GFAM:Synaptotagmins) association bp(GO:"GO:0031629") View Subject | View Object

Appears in Networks:
Annotations
MeSH
Cognitive Dysfunction

p(GFAM:Synaptotagmins) association bp(GO:"GO:0007269") View Subject | View Object

Appears in Networks:
Annotations
MeSH
Cognitive Dysfunction

path(MESH:D000544) decreases r(HGNC:SYP) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Cognitive Dysfunction

path(MESH:D000544) decreases r(GFAM:Synaptotagmins) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Cognitive Dysfunction

path(MESH:D000544) causesNoChange r(HGNC:VAMP1) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Cognitive Dysfunction

path(MESH:D000544) causesNoChange r(HGNC:SNAP29) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Cognitive Dysfunction

path(MESH:D000544) causesNoChange r(HGNC:APP) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Cognitive Dysfunction

path(MESH:D000544) causesNoChange r(HGNC:NOTCH1) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Cognitive Dysfunction

path(MESH:D000544) increases r(HGNC:CTSD) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Cognitive Dysfunction

Evidence 0f4e8e5c10
JSON

In addition, indirect effects and unwanted side effects appeared with systemic administration including unregulated neurotransmitter release, hyperinnervation, sprouting of neurons, sympathetic stimulation, induction of antibodies, cachexia and hyperalgesia [178–181].

bp(GO:"GO:0048485") association p(HGNC:NGF) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Cognitive Dysfunction

bp(GO:"GO:0007269") association p(HGNC:NGF) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Cognitive Dysfunction

bp(GO:"GO:0060384") association p(HGNC:NGF) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Cognitive Dysfunction

p(HGNC:NGF) association bp(GO:"GO:0060384") View Subject | View Object

Appears in Networks:
Annotations
MeSH
Cognitive Dysfunction

p(HGNC:NGF) association bp(GO:"GO:0007269") View Subject | View Object

Appears in Networks:
Annotations
MeSH
Cognitive Dysfunction

p(HGNC:NGF) association bp(GO:"GO:0048485") View Subject | View Object

Appears in Networks:
Annotations
MeSH
Cognitive Dysfunction

p(HGNC:NGF) association path(MESH:D002100) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Cognitive Dysfunction

p(HGNC:NGF) association path(MESH:D006930) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Cognitive Dysfunction

path(MESH:D002100) association p(HGNC:NGF) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Cognitive Dysfunction

path(MESH:D006930) association p(HGNC:NGF) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Cognitive Dysfunction

Evidence 02488bfff4
JSON

A second downstream pathway is the PI3K/Akt pathway that regulates neurotrophin-mediated survival responses in PC12 cells [90,91]. Regulation of this pathway involves upstream elements including Ras/Gab1/IRS1 [92,93].

p(FPLX:RAS) association bp(GO:"GO:0014065") View Subject | View Object

Appears in Networks:
Annotations
Experimental Factor Ontology (EFO)
PC12
MeSH
Cognitive Dysfunction

bp(GO:"GO:0014065") regulates bp(MESH:D002470) View Subject | View Object

Appears in Networks:
Annotations
Experimental Factor Ontology (EFO)
PC12
MeSH
Cognitive Dysfunction

bp(GO:"GO:0014065") association p(FPLX:RAS) View Subject | View Object

Appears in Networks:
Annotations
Experimental Factor Ontology (EFO)
PC12
MeSH
Cognitive Dysfunction

bp(GO:"GO:0014065") association p(HGNC:IRS1) View Subject | View Object

Appears in Networks:
Annotations
Experimental Factor Ontology (EFO)
PC12
MeSH
Cognitive Dysfunction

bp(GO:"GO:0014065") association p(HGNC:GAB1) View Subject | View Object

Appears in Networks:
Annotations
Experimental Factor Ontology (EFO)
PC12
MeSH
Cognitive Dysfunction

bp(GO:"GO:0043491") regulates bp(MESH:D002470) View Subject | View Object

Appears in Networks:
Annotations
Experimental Factor Ontology (EFO)
PC12
MeSH
Cognitive Dysfunction

bp(GO:"GO:0043491") association p(FPLX:RAS) View Subject | View Object

Appears in Networks:
Annotations
Experimental Factor Ontology (EFO)
PC12
MeSH
Cognitive Dysfunction

bp(GO:"GO:0043491") association p(HGNC:IRS1) View Subject | View Object

Appears in Networks:
Annotations
Experimental Factor Ontology (EFO)
PC12
MeSH
Cognitive Dysfunction

bp(GO:"GO:0043491") association p(HGNC:GAB1) View Subject | View Object

Appears in Networks:
Annotations
Experimental Factor Ontology (EFO)
PC12
MeSH
Cognitive Dysfunction

p(FPLX:RAS) association bp(GO:"GO:0043491") View Subject | View Object

Appears in Networks:
Annotations
Experimental Factor Ontology (EFO)
PC12
MeSH
Cognitive Dysfunction

p(HGNC:GAB1) association bp(GO:"GO:0014065") View Subject | View Object

Appears in Networks:
Annotations
Experimental Factor Ontology (EFO)
PC12
MeSH
Cognitive Dysfunction

p(HGNC:GAB1) association bp(GO:"GO:0043491") View Subject | View Object

Appears in Networks:
Annotations
Experimental Factor Ontology (EFO)
PC12
MeSH
Cognitive Dysfunction

p(HGNC:IRS1) association bp(GO:"GO:0014065") View Subject | View Object

Appears in Networks:
Annotations
Experimental Factor Ontology (EFO)
PC12
MeSH
Cognitive Dysfunction

p(HGNC:IRS1) association bp(GO:"GO:0043491") View Subject | View Object

Appears in Networks:
Annotations
Experimental Factor Ontology (EFO)
PC12
MeSH
Cognitive Dysfunction

Evidence 97dc7f3d4e
JSON

NGF is synthesized as a precursor (proNGF) molecule that is proteolytically cleaved to a mature biologically active neurotrophin peptide [49]. Mature NGF binds to the TrkA receptor, which stimulates signal transduction pathways mediating the majority of the survival and growth effects of NGF [50], and to the p75NTR receptor, which is a positive modulator of NGF/TrkA binding [50]. However, p75NTR has multiple functions, including apoptotic or cell death actions [51–56], which are dependent upon its interaction with various receptor chaperones [57–59].

bp(GO:"GO:0038180") increases bp(GO:"GO:1990089") View Subject | View Object

Appears in Networks:
Annotations
MeSH
Cognitive Dysfunction

bp(GO:"GO:1901214") association p(HGNC:NGFR) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Cognitive Dysfunction

p(HGNC:NGFR) association bp(GO:"GO:1901214") View Subject | View Object

Appears in Networks:
Annotations
MeSH
Cognitive Dysfunction

complex(p(HGNC:NGF), p(HGNC:NGFR)) increases complex(p(HGNC:NGF), p(HGNC:NTRK1)) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Cognitive Dysfunction

complex(p(HGNC:NGF), p(HGNC:NTRK1)) increases bp(GO:"GO:0038180") View Subject | View Object

Appears in Networks:
Annotations
MeSH
Cognitive Dysfunction

Evidence 8049a9cc91
JSON

Delaying or preventing cholinergic neurodegeneration or minimizing its consequences is the mechanism of action for most currently available US FDA-approved drugs for the treatment of cognitive dysfunction observed in AD [17]

bp(HBP:Neurodegeneration) association path(MESH:D060825) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Cholinergic Neurons

path(MESH:D060825) association bp(HBP:Neurodegeneration) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Cholinergic Neurons

Evidence 7d8980239f
JSON

In addition, subunits of protein phosphatase PP1 (Unigene-NCBI annotation PPP1CA and PPP1CC) mRNAs were downregulated in CBF neurons in AD [135]. This observation is interesting in light of the observation that PP1 can phosphorylate tau on several serine/threonine residues and experimental downregulation of PP1 activity leads to increased tau hyperphosphorylation [137,138], which may affect NFT formation in CBF neurons.

bp(HBP:hyperphosphorylation) association path(MESH:D016874) View Subject | View Object

Appears in Networks:
Annotations
Disease Ontology (DO)
Alzheimer's disease
MeSH
Cholinergic Neurons
MeSH
Cognitive Dysfunction

p(GFAM:"Protein phosphatase catalytic subunits") increases p(HGNC:MAPT, pmod(Ph)) View Subject | View Object

Appears in Networks:
Annotations
Disease Ontology (DO)
Alzheimer's disease
MeSH
Cholinergic Neurons
MeSH
Cognitive Dysfunction

act(p(GFAM:"Protein phosphatase catalytic subunits")) decreases bp(HBP:hyperphosphorylation) View Subject | View Object

Appears in Networks:
Annotations
Disease Ontology (DO)
Alzheimer's disease
MeSH
Cholinergic Neurons
MeSH
Cognitive Dysfunction

path(MESH:D000544) decreases r(HGNC:PPP1CA) View Subject | View Object

Appears in Networks:
Annotations
Disease Ontology (DO)
Alzheimer's disease
MeSH
Cholinergic Neurons
MeSH
Cognitive Dysfunction

path(MESH:D000544) decreases r(HGNC:PPP1CC) View Subject | View Object

Appears in Networks:
Annotations
Disease Ontology (DO)
Alzheimer's disease
MeSH
Cholinergic Neurons
MeSH
Cognitive Dysfunction

path(MESH:D016874) association bp(HBP:hyperphosphorylation) View Subject | View Object

Appears in Networks:
Annotations
Disease Ontology (DO)
Alzheimer's disease
MeSH
Cholinergic Neurons
MeSH
Cognitive Dysfunction

Evidence 96f348e536
JSON

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.

bp(MESH:D000375) increases p(HGNC:NGFR) View Subject | View Object

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

p(HGNC:NTRK1) decreases act(p(HGNC:BACE1)) View Subject | View Object

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

p(HGNC:NGFR) increases act(p(HGNC:BACE1)) View Subject | View Object

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

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

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

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

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

Evidence 7d06560bec
JSON

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]

bp(MESH:D009473) association act(p(HGNC:GAL)) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Cognitive Dysfunction

act(p(HGNC:GAL)) association path(MESH:D003071) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Cognitive Dysfunction

act(p(HGNC:GAL)) association bp(MESH:D009473) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Cognitive Dysfunction

act(p(HGNC:GAL)) increases bp(GO:"GO:0060384") View Subject | View Object

Appears in Networks:
Annotations
Disease Ontology (DO)
Alzheimer's disease
MeSH
Basal Forebrain
MeSH
Cholinergic Neurons
MeSH
Cognitive Dysfunction

act(p(HGNC:GAL)) regulates act(a(MESH:D059329)) View Subject | View Object

Appears in Networks:
Annotations
Disease Ontology (DO)
Alzheimer's disease
MeSH
Basal Forebrain
MeSH
Cholinergic Neurons
MeSH
Cognitive Dysfunction

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

Appears in Networks:
Annotations
Disease Ontology (DO)
Alzheimer's disease
MeSH
Basal Forebrain
MeSH
Cholinergic Neurons
MeSH
Cognitive Dysfunction

act(p(HGNC:GAL)) increases r(HGNC:CHAT) View Subject | View Object

Appears in Networks:
Annotations
Disease Ontology (DO)
Alzheimer's disease
MeSH
Basal Forebrain
MeSH
Cholinergic Neurons
MeSH
Cognitive Dysfunction

path(MESH:D003071) association act(p(HGNC:GAL)) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Cognitive Dysfunction

Evidence 52abe71bac
JSON

A third downstream mediator is the PLCgamma pathway [94,95]. PLCgamma pathway dysfunction may play a role in Ca2+-mediated cellular degeneration in aging and disease by affecting oxidative stress systems [96].

bp(MESH:D018384) association act(p(HGNC:PLCG1)) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Cognitive Dysfunction

bp(MESH:D018384) association path(MESH:D000375) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Cognitive Dysfunction

bp(MESH:D018384) association path(MESH:D009410) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Cognitive Dysfunction

act(p(HGNC:PLCG1)) association bp(MESH:D018384) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Cognitive Dysfunction

path(MESH:D000375) association bp(MESH:D018384) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Cognitive Dysfunction

path(MESH:D009410) association bp(MESH:D018384) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Cognitive Dysfunction

Evidence 561fc6cde4
JSON

Despite a putative beneficial role for increased CBF neuron alpha7 nAChR expression in AD (that may also be relevant to smoking behavior), evidence suggests that increased alpha7 nAChR expression contributes to cellular degeneration. Notably, alpha7 nAChR binds and/or interacts with APP and Ab peptides [123–125]. Increased NB neuronal alpha7 nAChR expression may arise as a compensatory response that is offset by aberrant Ab-alpha7 nAChR interactions, leading to cholinergic dysfunction.

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

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

complex(a(CHEBI:"amyloid-beta"), p(HGNC:CHRNA7)) decreases bp(GO:"GO:0007271") View Subject | View Object

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

p(HGNC:CHRNA7) increases complex(p(HGNC:APP), p(HGNC:CHRNA7)) View Subject | View Object

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

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

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

r(HGNC:CHRNA7) increases path(MESH:D009410) View Subject | View Object

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

Evidence 9fdd08df6e
JSON

By contrast, several studies indicate that increases in cortical proNGF may result in proapoptotic signaling through binding to the p75NTR receptor. In support of this, a different form of recombinant proNGF was shown to bind p75NTR with high affinity and promote neuronal apoptosis [55].

complex(a(MESHC:"pro-nerve growth factor, human"), p(HGNC:NGFR)) increases bp(GO:"GO:0006915") View Subject | View Object

Appears in Networks:
Annotations
MeSH
Cognitive Dysfunction

Evidence adfd717005
JSON

In this regard, immunoblotting studies demonstrated that proNGF is the predominant form of NGF present in the cortex of aged cognitively intact humans [60]. ProNGF levels are increased in the cortex of subjects diagnosed with MCI or mild AD compared to those with NCI [61]. The biological consequences of proNGF are controversial, as is the function of its accumulation in the cortex during the prodromal stages of AD. Emerging literature suggests that recombinant proNGF binds TrkA and promotes neuronal survival and neurite outgrowth similar to mature NGF, but is approximately fivefold less active than the mature NGF peptide [62,63].

complex(a(MESHC:"pro-nerve growth factor, human"), p(HGNC:NTRK1)) increases bp(GO:"GO:0031175") View Subject | View Object

Appears in Networks:
Annotations
MeSH
Cerebral Cortex
MeSH
Cognitive Dysfunction

complex(p(HGNC:NGF), p(HGNC:NTRK1)) increases bp(GO:"GO:0031175") View Subject | View Object

Appears in Networks:
Annotations
MeSH
Cerebral Cortex
MeSH
Cognitive Dysfunction

path(MESH:D000544) increases a(MESHC:"pro-nerve growth factor, human") View Subject | View Object

Appears in Networks:
Annotations
MeSH
Cerebral Cortex
MeSH
Cognitive Dysfunction

path(MESH:D060825) increases a(MESHC:"pro-nerve growth factor, human") View Subject | View Object

Appears in Networks:
Annotations
MeSH
Cerebral Cortex
MeSH
Cognitive Dysfunction

Evidence 2a9d549591
JSON

NGF therapy has been tested in clinical trials of diabetic peripheral neuropathy and HIV-associated neuropathy, as well as patients with AD [177]. Each of these clinical trials met with disappointment owing to lack of efficacy, toxicity or both.

p(HGNC:NGF) causesNoChange path(MESH:D003929) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Cognitive Dysfunction

p(HGNC:NGF) causesNoChange path(MESH:D016263) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Cognitive Dysfunction

p(HGNC:NGF) causesNoChange path(MESH:D000544) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Cognitive Dysfunction

Evidence 65eb9d9db5
JSON

The ex vivo Phase I trial attempted to move beyond currently available treatments for AD [113]. The goal of this NGF trial was to protect CBF neurons from degeneration, as well as augment the function of remaining cholinergic neurons by delivery of human NGF. After obtaining informed consent, skin biopsies were attained to generate primary cultures of autologous fibroblasts that were transfected to produce human NGF [184]. If fibroblasts were found to be acceptable based on NGF production rates, then grafts were stereotaxically placed into multiple locations within the region of the CBF neurons. Following a period of 22 months, no long-term post-surgical adverse effects were found and the rate of cognitive decline appeared to be reduced [113].

p(HGNC:NGF) decreases path(MESH:D060825) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Fibroblasts
MeSH
Cognitive Dysfunction

g(HGNC:NGF) directlyIncreases p(HGNC:NGF) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Fibroblasts
MeSH
Cognitive Dysfunction

Evidence c0910db9fa
JSON

Recent findings indicate that the putative proapoptotic effect(s) of p75NTR-mediated proNGF signaling is dependent on interactions between p75NTR and the neurotensin receptor sortilin, a Vps10p domain trafficking protein that acts as a cell surface coreceptor with p75NTR to mediate proNGF-induced cell death. This family of receptors is acquiring increasing importance owing to its potential involvement in AD [68]. A recent study provided genetic information for a role of the proneurotrophin receptor complex comprising sortilin and p75NTR, in the mediation of neuronal viability in vivo [69]. Sortilin expression is required for p75NTR-mediated apoptosis following proNGF treatment [57], suggesting that sortilin is a p75NTR binding partner associated with the initiation of cell death [51,58]

p(HGNC:SORT1) association path(MESH:D000544) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Cognitive Dysfunction

composite(a(MESHC:"pro-nerve growth factor, human"), complex(p(HGNC:NGFR), p(HGNC:SORT1))) increases bp(GO:"GO:0006915") View Subject | View Object

Appears in Networks:
Annotations
MeSH
Cognitive Dysfunction

path(MESH:D000544) association p(HGNC:SORT1) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Cognitive Dysfunction

Evidence 136fcf51b5
JSON

These studies have demonstrated a significant downregulation of trkA, trkB and trkC gene expression during the development of AD [7]. An intermediate reduction was observed in MCI, with the greatest decrement in mild AD compared to aged controls. Moreover, two separate expressed sequence tag (EST) cDNAs for each trk gene (e.g., ESTs targeted to the extracellular domain [ECD] and tyrosine kinase [TK]) domains were downregulated. By contrast, there was a lack of regulation of p75NTR expression [7] in CBF neurons. A ‘step down’ dysregulation of trk expression may, in part, underlie CBF neuron demise associated with the clinical presentation of AD. Supporting this concept is the finding that trk downregulation is associated with measures of cognitive decline [7,14]

g(HGNC:NTRK1) association path(MESH:D003071) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Basal Forebrain
MeSH
Cholinergic Neurons
MeSH
Cognitive Dysfunction

g(HGNC:NTRK2) association path(MESH:D003071) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Basal Forebrain
MeSH
Cholinergic Neurons
MeSH
Cognitive Dysfunction

g(HGNC:NTRK3) association path(MESH:D003071) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Basal Forebrain
MeSH
Cholinergic Neurons
MeSH
Cognitive Dysfunction

path(MESH:D000544) decreases g(HGNC:NTRK1) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Basal Forebrain
MeSH
Cholinergic Neurons
MeSH
Cognitive Dysfunction

path(MESH:D000544) decreases g(HGNC:NTRK2) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Basal Forebrain
MeSH
Cholinergic Neurons
MeSH
Cognitive Dysfunction

path(MESH:D000544) decreases g(HGNC:NTRK3) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Basal Forebrain
MeSH
Cholinergic Neurons
MeSH
Cognitive Dysfunction

path(MESH:D000544) increases g(HGNC:NGFR) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Basal Forebrain
MeSH
Cholinergic Neurons
MeSH
Cognitive Dysfunction

path(MESH:D003071) association g(HGNC:NTRK1) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Basal Forebrain
MeSH
Cholinergic Neurons
MeSH
Cognitive Dysfunction

path(MESH:D003071) association g(HGNC:NTRK2) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Basal Forebrain
MeSH
Cholinergic Neurons
MeSH
Cognitive Dysfunction

path(MESH:D003071) association g(HGNC:NTRK3) View Subject | View Object

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MeSH
Basal Forebrain
MeSH
Cholinergic Neurons
MeSH
Cognitive Dysfunction

Evidence d4b677e94c
JSON

In this regard, AChE has been localized to SPs in the vicinity of cholinergic synapses, and experimental evidence suggests that AChE promotes Ab fibrillization [164], suggesting that a further benefit from AChE inhibitor therapy may be to prevent continued Ab deposition in cholinergic projection sites.

p(HGNC:ACHE) association path(MESH:D058225) View Subject | View Object

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MeSH
Cognitive Dysfunction

p(HGNC:ACHE) increases bp(GO:"GO:1990000") View Subject | View Object

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MeSH
Cognitive Dysfunction

path(MESH:D058225) association p(HGNC:ACHE) View Subject | View Object

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MeSH
Cognitive Dysfunction

Evidence 9cc11367d6
JSON

In MCI, increased hippocampal and frontal cortex ChAT tone may be important for promoting biochemical activity or compensating for neurodegenerative defects, which may delay the transition of these subjects to frank AD. Hippocampal ChAT activity was increased selectively in MCI cases with high Braak scores (Braak III/IV stage) indicative of advanced disease [19], suggesting that a compensatory upregulation of ChAT may be due, at least in part, to the disconnection of glutamatergic entorhinal cortex input to the hippocampus which occurs early in the disease process [21–23]. In this scenario, upregulation of hippocampal ChAT activity may be due to reactive synaptogenesis, the filling in of denervated glutamatergic synapses by cholinergic input arising from the septum [24].

act(p(HGNC:CHAT)) decreases bp(HBP:Neurodegeneration) View Subject | View Object

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MeSH
Frontal Lobe
MeSH
Hippocampus
MeSH
Cognitive Dysfunction

path(MESH:D060825) increases act(p(HGNC:CHAT)) View Subject | View Object

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MeSH
Frontal Lobe
MeSH
Hippocampus
MeSH
Cognitive Dysfunction

path(MESH:D060825) decreases a(MESH:D013569) View Subject | View Object

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MeSH
Frontal Lobe
MeSH
Hippocampus
MeSH
Cognitive Dysfunction

Evidence f3caa96f0d
JSON

Conversely, M1 subunit gene expression in single CBF neurons is preserved during the progression of AD (Table 1) [119,126]. The M1 receptor is a most interesting drug target as it links several of the major hallmarks of this disorder, including cholinergic deficiency, cognitive dysfunctions, Ab and tau pathologies.

p(HGNC:CHRM1) association path(MESH:D060825) View Subject | View Object

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

p(HGNC:CHRM1) association path(MESH:D024801) View Subject | View Object

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

p(HGNC:CHRM1) association path(MESH:D000686) View Subject | View Object

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

path(MESH:D000544) causesNoChange r(HGNC:CHRM1) View Subject | View Object

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

path(MESH:D000686) association p(HGNC:CHRM1) View Subject | View Object

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

path(MESH:D024801) association p(HGNC:CHRM1) View Subject | View Object

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

path(MESH:D060825) association p(HGNC:CHRM1) View Subject | View Object

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

Evidence f782558eb7
JSON

We found an upregulation of MMP-9 protein levels and activity in both AD and MCI brains, which correlated inversely with cognitive status (Figure 1B) [75]. Since tissue alterations are often reflected in bodily fluids, determination of MMPs in blood, urine and CSF has been recommended as potential biomarkers to act as diagnostic measures to characterize the disease process that occurs in the brain [76–78]. Interestingly, plasma MMP-9 was increased in MCI and AD [77].

act(p(HGNC:MMP9)) positiveCorrelation path(MESH:D003072) View Subject | View Object

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MeSH
Brain
MeSH
Plasma
MeSH
Cognitive Dysfunction

path(MESH:D000544) increases act(p(HGNC:MMP9)) View Subject | View Object

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MeSH
Brain
MeSH
Plasma
MeSH
Cognitive Dysfunction

path(MESH:D003072) positiveCorrelation act(p(HGNC:MMP9)) View Subject | View Object

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MeSH
Brain
MeSH
Plasma
MeSH
Cognitive Dysfunction

path(MESH:D060825) increases act(p(HGNC:MMP9)) View Subject | View Object

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MeSH
Brain
MeSH
Plasma
MeSH
Cognitive Dysfunction

Evidence fcf53f9147
JSON

In this vein, intraventricular infusion of NGF increased hippocampal GAL mRNA expression in rats [158], suggesting that the use of NGF for the treatment of AD [113] may indirectly increase brain GAL providing a dual therapeutic benefit for the treatment of CBF dysfunction in AD.

p(RGD:Ngf) increases r(RGD:Gal) View Subject | View Object

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MeSH
Cognitive Dysfunction

p(RGD:Ngf) decreases path(MESH:D060825) View Subject | View Object

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MeSH
Cognitive Dysfunction

Evidence 73a96d2a57
JSON

People with a clinical diagnosis of MCI comprise a heterogeneous cohort of which those with memory deficits only are classified as amnestic MCI (aMCI) and those with impairment in other cognitive domains lacking a clinical diagnosis of dementia are designated multidomain MCI (mdMCI) [3,4]. Many individuals characterized with aMCI progress steadily to greater stages of dementia severity, and in many instances exhibit the neuropathologic, molecular and biochemical hallmarks of AD [5–9]. These clinical pathobiologic studies suggest that MCI, in general, represents a prodromal or preclinical stage of AD.

path(HBP:aMCI) association path(MESH:D008569) View Subject | View Object

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path(HBP:aMCI) association path(MESH:D003704) View Subject | View Object

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path(HBP:aMCI) association path(MESH:D000544) View Subject | View Object

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path(HBP:mdMCI) association path(MESH:D060825) View Subject | View Object

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path(MESH:D000544) association path(HBP:aMCI) View Subject | View Object

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path(MESH:D003704) association path(HBP:aMCI) View Subject | View Object

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path(MESH:D008569) association path(HBP:aMCI) View Subject | View Object

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path(MESH:D060825) association path(HBP:mdMCI) View Subject | View Object

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path(MESH:D060825) association path(MESH:D062706) View Subject | View Object

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Annotations
Disease Ontology (DO)
Alzheimer's disease

path(MESH:D062706) association path(MESH:D060825) View Subject | View Object

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

Evidence 9c512e53ca
JSON

Alzheimer’s disease (AD) is a progressive and fatal neurodegenerative disorder manifested by cognitive and memory decline and progressive impairment of activities of daily living, as well as a variety of neuropsychiatric symptoms and behavioral dysfunctions.

path(MESH:D001526) association path(MESH:D000544) View Subject | View Object

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path(MESH:D000544) association path(MESH:D019636) View Subject | View Object

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path(MESH:D000544) association path(MESH:D008568) View Subject | View Object

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path(MESH:D000544) association path(MESH:D003071) View Subject | View Object

Appears in Networks:

path(MESH:D000544) association path(MESH:D001526) View Subject | View Object

Appears in Networks:

path(MESH:D003071) association path(MESH:D000544) View Subject | View Object

Appears in Networks:

path(MESH:D008568) association path(MESH:D000544) View Subject | View Object

Appears in Networks:

path(MESH:D019636) association path(MESH:D000544) View Subject | View Object

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Evidence 15f221275c
JSON

Although there is a widespread decline in various neurotransmitter containing cell bodies in end-stage AD, the most consistent losses throughout the progression of AD are seen in long projection neurons, including cholinergic neurons of the basal forebrain [11–13]

path(MESH:D000544) decreases a(MESH:D059329) View Subject | View Object

Appears in Networks:
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Disease Ontology (DO)
Alzheimer's disease
MeSH
Basal Forebrain

Evidence e8d9da4059
JSON

For example, the vesicular ACh transporter (VAChT), which is co-expressed with ChAT in human CBF neurons and participates in loading ACh into synaptic vesicles in cholinergic terminals, is not severely altered in AD [40]. In this regard, pharmacological studies of VAChT in postmortem AD tissue or in vivo imaging studies using vesamicol and its analogs, suggest that VAChT levels remain steady or are minimally decreased coincident with a severe decline in ChAT activity in cortical areas [41].

path(MESH:D000544) decreases act(p(HGNC:ACHE)) View Subject | View Object

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MeSH
Cognitive Dysfunction

path(MESH:D000544) causesNoChange p(HGNC:SLC18A3) View Subject | View Object

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MeSH
Cognitive Dysfunction

Evidence 3c62f9cb81
JSON

Moreover, there is evidence from experimental lesions in animals [43–45] and from postmortem human brain studies [46,47] suggesting that many cholinergic neurons shrink, are depleted of phenotypic markers, and/or persist in an atrophic state after injury or during the pathological process, rather than degenerate.

path(MESH:D000544) increases path(MESH:D001284) View Subject | View Object

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MeSH
Cholinergic Neurons
MeSH
Cognitive Dysfunction

Evidence afc3fc6766
JSON

Bruno and Cuello reported that a protease cascade which converts proNGF to mature NGF (mNGF) and degrades mNGF in the extracellular space by the coordinated activity of plasminogen, tissue plasminogen activator (tPA), neuroserpin, matrix metalloproteinase (MMP)-9 and tissue inhibitor of MMP (TIMP)-1 may be defective in AD, resulting in NGF dysfunction [74].

path(MESH:D000544) decreases bp(GO:"GO:0032455") View Subject | View Object

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MeSH
Cognitive Dysfunction

Evidence 7711156c44
JSON

Single cell expression via microarray analysis was used to determine whether expression levels for nAChR and mAChR receptors, as well as ChAT, were differentially regulated within individual CBF neurons harvested from NCI, MCI and AD cases. ChAT mRNA expression levels did not differ across clinical conditions (Table 1). However, there was a significant upregulation of alpha7 nAChR subunit expression in AD compared with NCI and MCI.

path(MESH:D000544) causesNoChange r(HGNC:CHAT) View Subject | View Object

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MeSH
Cholinergic Neurons
MeSH
Cognitive Dysfunction

path(MESH:D000544) increases r(HGNC:CHRNA7) View Subject | View Object

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Annotations
MeSH
Cholinergic Neurons
MeSH
Cognitive Dysfunction

path(MESH:D060825) causesNoChange r(HGNC:CHAT) View Subject | View Object

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Annotations
MeSH
Cholinergic Neurons
MeSH
Cognitive Dysfunction

Evidence aee741f910
JSON

This increase in alpha7 nAChR expression levels within CBF neurons was inversely associated with cognitive performance. Increased alpha7 nAChR expression in CBF neurons may signal a compensatory response to maintain basocortical cholinergic activity during the onset of AD. Upregulation of the alpha7 nAChR within individual CBF neurons is also consistent with reports of increased alpha7 nAChR mRNA and protein expression levels in hippocampal neurons, astrocytes and peripheral blood leukocytes in AD [120–122]. The observed increase in alpha7 nAChR in early AD may regulate basocortical cholinergic tone through pre- and/or postsynaptic mechanisms within cholinergic NB neurons prior to their frank degeneration in the later stages of AD.

path(MESH:D000544) increases r(HGNC:CHRNA7) View Subject | View Object

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Annotations
Disease Ontology (DO)
Alzheimer's disease
MeSH
Astrocytes
MeSH
Hippocampus
MeSH
Leukocytes
MeSH
Cognitive Dysfunction

path(MESH:D003071) negativeCorrelation r(HGNC:CHRNA7) View Subject | View Object

Appears in Networks:
Annotations
Disease Ontology (DO)
Alzheimer's disease
MeSH
Astrocytes
MeSH
Hippocampus
MeSH
Leukocytes
MeSH
Cognitive Dysfunction

r(HGNC:CHRNA7) negativeCorrelation path(MESH:D003071) View Subject | View Object

Appears in Networks:
Annotations
Disease Ontology (DO)
Alzheimer's disease
MeSH
Astrocytes
MeSH
Hippocampus
MeSH
Leukocytes
MeSH
Cognitive Dysfunction

r(HGNC:CHRNA7) regulates act(a(MESH:D059329)) View Subject | View Object

Appears in Networks:
Annotations
Disease Ontology (DO)
Alzheimer's disease
MeSH
Cholinergic Neurons
MeSH
Cognitive Dysfunction

Evidence 3a752419be
JSON

Cortical and CBF neurons display NFT formation in the MCI brain [9,139,140], suggesting a concomitant alteration in tau gene expression during the early stage of AD. The adult human brain contains six tau isoforms ranging from 48 to 67 kDa, which are expressed through alternative splicing of a single tau gene on chromosome 17 [141,142]. Three of these tau isoforms contain three tandem repeats in the carboxy-terminus end of the molecule (3Rtau), while three isoforms display four tandem repeats (4Rtau) in this region. Expression levels of the six tau transcripts within CBF neurons do not differ significantly during the progression of AD [6]

path(MESH:D000544) increases path(MESH:D016874) View Subject | View Object

Appears in Networks:
Annotations
Disease Ontology (DO)
Alzheimer's disease
MeSH
Cerebral Cortex
MeSH
Cholinergic Neurons
MeSH
Cognitive Dysfunction

path(MESH:D000544) causesNoChange r(HGNC:MAPT) View Subject | View Object

Appears in Networks:
Annotations
Disease Ontology (DO)
Alzheimer's disease
MeSH
Cerebral Cortex
MeSH
Cholinergic Neurons
MeSH
Cognitive Dysfunction

Evidence 0af3fa4c6a
JSON

However, a calculation of the ratio of 3Rtau/4Rtau revealed a significant shift in the 3Rtau/4Rtau ratio, with a decrement in 3Rtau in relation to 4Rtau levels for each tau transcript analyzed within CBF perikarya obtained from MCI and AD cases (Table 1) [6]. A similar shift did not occur during normal aging. These data suggest a subtle, yet pervasive shift in the gene dosage of 3Rtau and 4Rtau within vulnerable CBF neurons in MCI and AD [6]. Shifts in the ratio of tau transcripts may be a fundamental mechanism whereby normal tau function is dysregulated, not only in CBF neurons, but may be a more widespread process contributing to the selective vulnerability of neurons to NFT formation (Figure 1B) [143–145].

path(MESH:D000544) decreases a(HBP:"3R tau") View Subject | View Object

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

path(MESH:D060825) decreases a(HBP:"3R tau") View Subject | View Object

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

Evidence ae8c274c90
JSON

The enzyme that hydrolyzes ACh at the synapse, AChE, does not show a decline in cortical areas until at least moderately severe levels of dementia [28].

path(MESH:D003704) decreases p(HGNC:ACHE) View Subject | View Object

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Evidence e842f5e14d
JSON

In fact, our group found elevated ChAT activity in the hippocampus and frontal cortex of subjects with MCI [19,20]. These results suggest that cognitive deficits in MCI and early AD are not associated with a reduction in ChAT activity. Moreover, these data indicate that select components of the hippocampal and cortical cholinergic projection system are capable of compensatory and/ or neuroplasticity responses during the early stages of AD.

path(MESH:D060825) increases act(p(HGNC:CHAT)) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Frontal Lobe
MeSH
Hippocampus

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.