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path(MESH:D060825)

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Entity

Name
D060825
Namespace
MeSH
Namespace Version
20181007
Namespace URL
https://raw.githubusercontent.com/pharmacome/terminology/01c9daa61012b37dd0a1bc962521ba51a15b38f1/external/mesh.belns

Appears in Networks 1

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

In-Edges 7

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

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]. PubMed:18986241

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

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

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] PubMed:18986241

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Annotations
MeSH
Cholinergic Neurons

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

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]. PubMed:18986241

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Annotations
MeSH
Fibroblasts
MeSH
Cognitive Dysfunction

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

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. PubMed:18986241

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

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

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. PubMed:18986241

Appears in Networks:
Annotations
MeSH
Cognitive Dysfunction

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

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. PubMed:18986241

Appears in Networks:

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

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. PubMed:18986241

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

Out-Edges 12

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

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. PubMed:18986241

Appears in Networks:

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

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. PubMed:18986241

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

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

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] PubMed:18986241

Appears in Networks:
Annotations
MeSH
Cholinergic Neurons

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

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]. PubMed:18986241

Appears in Networks:
Annotations
MeSH
Neocortex
MeSH
Cognitive Dysfunction

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

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. PubMed:18986241

Appears in Networks:
Annotations
MeSH
Frontal Lobe
MeSH
Hippocampus

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

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]. PubMed:18986241

Appears in Networks:
Annotations
MeSH
Frontal Lobe
MeSH
Hippocampus
MeSH
Cognitive Dysfunction

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

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]. PubMed:18986241

Appears in Networks:
Annotations
MeSH
Frontal Lobe
MeSH
Hippocampus
MeSH
Cognitive Dysfunction

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

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]. PubMed:18986241

Appears in Networks:
Annotations
MeSH
Cerebral Cortex
MeSH
Cognitive Dysfunction

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

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]. PubMed:18986241

Appears in Networks:
Annotations
MeSH
Brain
MeSH
Plasma
MeSH
Cognitive Dysfunction

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

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. PubMed:18986241

Appears in Networks:
Annotations
MeSH
Cholinergic Neurons
MeSH
Cognitive Dysfunction

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

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. PubMed:18986241

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

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

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]. PubMed:18986241

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

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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.