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path(MESH:D000544)

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Entity

Name
D000544
Namespace
mesh
Namespace Version
20180828
Namespace URL
https://raw.githubusercontent.com/pharmacome/terminology/1b20f0637c395f8aa89c2e2e342d7b704062c242/external/mesh.belns

Appears in Networks 2

Interplay of neurotransmitters in Alzheimer's disease v1.0.0

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

In-Edges 16

bp(GO:"GO:0070997") association path(MESH:D000544) View Subject | View Object

From the perspective of brain histopathology, Alzheimer's disease has three characteristic features—the appearance of beta-amyloid plaques, the presence of neurofibrillary tangles, and the loss of neuronal cells PubMed:16273023

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Disease Ontology (DO)
Alzheimer's disease

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

From the perspective of brain histopathology, Alzheimer's disease has three characteristic features—the appearance of beta-amyloid plaques, the presence of neurofibrillary tangles, and the loss of neuronal cells PubMed:16273023

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

path(MESH:D058225) association path(MESH:D000544) View Subject | View Object

From the perspective of brain histopathology, Alzheimer's disease has three characteristic features—the appearance of beta-amyloid plaques, the presence of neurofibrillary tangles, and the loss of neuronal cells PubMed:16273023

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Disease Ontology (DO)
Alzheimer's disease

a(CHEBI:physostigmine) decreases path(MESH:D000544) 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

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Annotations
Disease Ontology (DO)
Alzheimer's disease

a(MESH:D002800) decreases path(MESH:D000544) 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
Disease Ontology (DO)
Alzheimer's disease

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

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]. PubMed:18986241

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

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

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]. PubMed:18986241

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

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

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. PubMed:18986241

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MeSH
Cognitive Dysfunction

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

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. PubMed:18986241

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Annotations
MeSH
Cognitive Dysfunction

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

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. PubMed:18986241

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Annotations
MeSH
Cognitive Dysfunction

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

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] PubMed:18986241

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Annotations
MeSH
Cognitive Dysfunction

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

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. PubMed:18986241

Appears in Networks:

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

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. PubMed:18986241

Appears in Networks:

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

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. PubMed:18986241

Appears in Networks:

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

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. PubMed:18986241

Appears in Networks:

Out-Edges 59

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

From the perspective of brain histopathology, Alzheimer's disease has three characteristic features—the appearance of beta-amyloid plaques, the presence of neurofibrillary tangles, and the loss of neuronal cells PubMed:16273023

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

path(MESH:D000544) association path(MESH:D058225) View Subject | View Object

From the perspective of brain histopathology, Alzheimer's disease has three characteristic features—the appearance of beta-amyloid plaques, the presence of neurofibrillary tangles, and the loss of neuronal cells PubMed:16273023

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

path(MESH:D000544) association bp(GO:"GO:0070997") View Subject | View Object

From the perspective of brain histopathology, Alzheimer's disease has three characteristic features—the appearance of beta-amyloid plaques, the presence of neurofibrillary tangles, and the loss of neuronal cells PubMed:16273023

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

path(MESH:D000544) decreases bp(MESH:D009435) View Subject | View Object

Although the loss of neurons leads to deficits in neurotransmission, even neurons that are not dead may exhibit impaired neurotransmission in Alzheimer's disease PubMed:16273023

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

path(MESH:D000544) decreases bp(GO:"GO:0007271") View Subject | View Object

Among the systems affected in patients with Alzheimer's disease are the cholinergic and glutamatergic neurotransmission systems. These two systems play key roles in cognition and, as a result, contemporary pharmacologic agents used in the treatment of Alzheimer's disease are designed to restore their functioning PubMed:16273023

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

path(MESH:D000544) decreases bp(GO:"GO:0035249") View Subject | View Object

Among the systems affected in patients with Alzheimer's disease are the cholinergic and glutamatergic neurotransmission systems. These two systems play key roles in cognition and, as a result, contemporary pharmacologic agents used in the treatment of Alzheimer's disease are designed to restore their functioning PubMed:16273023

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

path(MESH:D000544) decreases act(p(HGNC:CHAT), ma(cat)) View Subject | View Object

For example, the activity of choline acetyltransferase, the enzyme that catalyzes the synthesis of ACh from choline and acetyl coenzyme A, is reduced to 35% to 50% of normal levels in Alzheimer's disease PubMed:16273023

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

path(MESH:D000544) decreases bp(GO:"GO:0015871") View Subject | View Object

Furthermore, synaptic reuptake of choline, which is essential for the synthesis of ACh molecules that are to be released into the synaptic cleft in subsequent rounds of neurotransmission, is reduced to -60% of normal levels in Alzheimer's disease, and direct measurement reveals that levels of ACh synthesis are reduced by one half in affected patients. PubMed:16273023

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

path(MESH:D000544) decreases bp(GO:"GO:0008292") View Subject | View Object

Furthermore, synaptic reuptake of choline, which is essential for the synthesis of ACh molecules that are to be released into the synaptic cleft in subsequent rounds of neurotransmission, is reduced to -60% of normal levels in Alzheimer's disease, and direct measurement reveals that levels of ACh synthesis are reduced by one half in affected patients. PubMed:16273023

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

path(MESH:D000544) causesNoChange p(MESH:D011950) View Subject | View Object

Despite the various cholinergic abnormalities seen in Alzheimer's disease, ACh receptor systems remain relatively unaltered in affected patients.8 PubMed:16273023

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path(MESH:D000544) decreases bp(GO:"GO:0051935") View Subject | View Object

In patients with Alzheimer's disease, available evidence points to a disruption in the glutamatergic neurotransmission cycle at the point of glial cell reuptake of free glutamate from the synapse. Neuropathologic studies have documented reduced levels of glutamate reuptake in the frontal and temporal cortices of patients with Alzheimer's disease,10 possibly due to oxidative modification of the glutamate transporter 1 molecule. Furthermore, diminished uptake by vesicular glutamate transporter has been reported in patients with Alzheimer's disease PubMed:16273023

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Annotations
Cell Ontology (CL)
glial cell
Disease Ontology (DO)
Alzheimer's disease
MeSH
Frontal Lobe
MeSH
Temporal Lobe

path(MESH:D000544) decreases bp(GO:"GO:0014047") View Subject | View Object

In patients with Alzheimer's disease, available evidence points to a disruption in the glutamatergic neurotransmission cycle at the point of glial cell reuptake of free glutamate from the synapse. Neuropathologic studies have documented reduced levels of glutamate reuptake in the frontal and temporal cortices of patients with Alzheimer's disease,10 possibly due to oxidative modification of the glutamate transporter 1 molecule. Furthermore, diminished uptake by vesicular glutamate transporter has been reported in patients with Alzheimer's disease PubMed:16273023

Appears in Networks:
Annotations
Cell Ontology (CL)
glial cell
Disease Ontology (DO)
Alzheimer's disease
MeSH
Frontal Lobe
MeSH
Temporal Lobe

path(MESH:D000544) decreases bp(GO:"GO:0014047") View Subject | View Object

Second, because of this background signal, as well as the fact that neurons are left with smaller amounts of neurotransmitter to release into the synapse during neuronal firing, the 'peak signal'—the difference between synaptic glutamate concentration during neuronal activity and synaptic glutamate concentration under resting conditions—is attenuated, leading to suboptimal neurotransmission as exemplified by a lack of long-term potentiation (LTP) PubMed:16273023

Appears in Networks:
Annotations
Cell Ontology (CL)
glial cell
Disease Ontology (DO)
Alzheimer's disease
MeSH
Frontal Lobe
MeSH
Temporal Lobe

path(MESH:D000544) decreases bp(MESH:D017774) View Subject | View Object

Second, because of this background signal, as well as the fact that neurons are left with smaller amounts of neurotransmitter to release into the synapse during neuronal firing, the 'peak signal'—the difference between synaptic glutamate concentration during neuronal activity and synaptic glutamate concentration under resting conditions—is attenuated, leading to suboptimal neurotransmission as exemplified by a lack of long-term potentiation (LTP) PubMed:16273023

Appears in Networks:
Annotations
Cell Ontology (CL)
glial cell
Disease Ontology (DO)
Alzheimer's disease
MeSH
Frontal Lobe
MeSH
Temporal Lobe

path(MESH:D000544) decreases bp(MESH:D017774) View Subject | View Object

It is believed that LTP, which can persist at a given synapse for periods ranging from hours to months, models the processes of learning and memory, and a number of studies have demonstrated a loss of LTP in animal models of Alzheimer's disease. PubMed:16273023

Appears in Networks:
Annotations
Cell Ontology (CL)
glial cell
MeSH
Frontal Lobe
MeSH
Temporal Lobe

path(MESH:D000544) decreases complex(a(CHEBI:"magnesium(2+)"), p(GFAM:"Glutamate ionotropic receptor NMDA type subunits")) View Subject | View Object

In Alzheimer's disease, however, it is believed that Mg2+ is displaced from the NMDA receptor calcium channel even under resting conditions, due to the elevated levels of glutamate that are present in the synapse at all times.13 It has been hypothesized that this constant activation of NMDA receptors leads to neuronal overactivity while also contributing to an unfavorable signal-to-noise ratio during glutamatergic neurotransmission and, hence, to the absence of LTP. PubMed:16273023

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

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

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. PubMed:18986241

Appears in Networks:

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

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. PubMed:18986241

Appears in Networks:

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

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. PubMed:18986241

Appears in Networks:

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

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. PubMed:18986241

Appears in Networks:

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

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] PubMed:18986241

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

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

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]. PubMed:18986241

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

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

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 PubMed:18986241

Appears in Networks:

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

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]. PubMed:18986241

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

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

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 PubMed:18986241

Appears in Networks:

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

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 PubMed:18986241

Appears in Networks:

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

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]. PubMed:18986241

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

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]. PubMed:18986241

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

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]. PubMed:18986241

Appears in Networks:
Annotations
MeSH
Cognitive Dysfunction

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

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]. PubMed:18986241

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

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

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]. PubMed:18986241

Appears in Networks:
Annotations
MeSH
Cognitive Dysfunction

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

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. PubMed:18986241

Appears in Networks:
Annotations
MeSH
Cholinergic Neurons
MeSH
Cognitive Dysfunction

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

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]. PubMed:18986241

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

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

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. PubMed:18986241

Appears in Networks:
Annotations
MeSH
Cerebrospinal Fluid
MeSH
Cognitive Dysfunction

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

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] PubMed:18986241

Appears in Networks:
Annotations
MeSH
Cognitive Dysfunction

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

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]. PubMed:18986241

Appears in Networks:
Annotations
MeSH
Cognitive Dysfunction

path(MESH:D000544) 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

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Annotations
MeSH
Brain
MeSH
Plasma
MeSH
Cognitive Dysfunction

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

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] PubMed:18986241

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

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

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] PubMed:18986241

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MeSH
Basal Forebrain
MeSH
Cholinergic Neurons
MeSH
Cognitive Dysfunction

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

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] PubMed:18986241

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MeSH
Basal Forebrain
MeSH
Cholinergic Neurons
MeSH
Cognitive Dysfunction

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

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] PubMed:18986241

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MeSH
Basal Forebrain
MeSH
Cholinergic Neurons
MeSH
Cognitive Dysfunction

path(MESH:D000544) 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

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MeSH
Cholinergic Neurons
MeSH
Cognitive Dysfunction

path(MESH:D000544) increases r(HGNC:CHRNA7) 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

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MeSH
Cholinergic Neurons
MeSH
Cognitive Dysfunction

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

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. PubMed:18986241

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

path(MESH:D000544) causesNoChange r(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

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

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

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]. PubMed:18986241

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Cognitive Dysfunction

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

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]. PubMed:18986241

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MeSH
Cognitive Dysfunction

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

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]. PubMed:18986241

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Annotations
MeSH
Cognitive Dysfunction

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

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]. PubMed:18986241

Appears in Networks:
Annotations
MeSH
Cognitive Dysfunction

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

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]. PubMed:18986241

Appears in Networks:
Annotations
MeSH
Cognitive Dysfunction

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

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]. PubMed:18986241

Appears in Networks:
Annotations
MeSH
Cognitive Dysfunction

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

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]. PubMed:18986241

Appears in Networks:
Annotations
MeSH
Cognitive Dysfunction

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

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. PubMed:18986241

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

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

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. PubMed:18986241

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

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

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] PubMed:18986241

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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

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] PubMed:18986241

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

path(MESH:D000544) 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

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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.