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PubMed: 16273023

Title
The interplay of neurotransmitters in Alzheimer's disease.
Journal
CNS spectrums
Volume
10
Issue
None
Pages
6-9
Date
2005-11-01
Authors
Francis PT

Evidence 3d30810e13
JSON

ChEIs are believed to target cholinergic abnormalities in Alzheimer's disease, although there is evidence indicating that their therapeutic effect may be via the glutamatergic system. NMDA receptor antagonists, in contrast, are believed to target the glutamatergic system directly

a(CHEBI:"NMDA receptor antagonist") association bp(GO:"GO:0035249") View Subject | View Object

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a(MESH:D002800) association bp(GO:"GO:0007271") View Subject | View Object

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bp(GO:"GO:0007271") association a(MESH:D002800) View Subject | View Object

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bp(GO:"GO:0035249") association a(CHEBI:"NMDA receptor antagonist") View Subject | View Object

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Evidence 3200c9b354
JSON

With regard to the glutamatergic system, studies suggest that ChEIs may stimulate the release of glutamate from pyramidal neurons during normal neuronal activity, while NMDA receptor antagonists are believed to block the abnormal neuronal activity that results from the presence of excess glutamate in the synapse under resting conditions. Thus, ChEIs and NMDA receptor antagonists appear to have complementary effects, as the former enhance the signals received by postsynaptic neurons during normal neurotransmission, and the latter diminish the background 'noise' that is constantly being detected by those same receptors.

a(CHEBI:"NMDA receptor antagonist") decreases act(a(MESH:D009474)) View Subject | View Object

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Annotations
Cell Ontology (CL)
pyramidal neuron

a(MESH:D002800) increases bp(GO:"GO:0014047") View Subject | View Object

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Annotations
Cell Ontology (CL)
pyramidal neuron

Evidence d43cb6479c
JSON

The capacity for thinking and remembering is derived from various input and output pathways between the hippocampus and the neocortex,9 and all such pathways rely on signaling mediated by the neurotransmitter glutamate.

a(CHEBI:"glutamate(1-)") association path(MESH:D013850) View Subject | View Object

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a(CHEBI:"glutamate(1-)") association path(MESH:D008568) View Subject | View Object

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a(MESH:D006624) association path(MESH:D013850) View Subject | View Object

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a(MESH:D006624) association path(MESH:D008568) View Subject | View Object

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a(MESH:D019579) association path(MESH:D013850) View Subject | View Object

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a(MESH:D019579) association path(MESH:D008568) View Subject | View Object

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path(MESH:D008568) association a(MESH:D006624) View Subject | View Object

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path(MESH:D008568) association a(MESH:D019579) View Subject | View Object

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path(MESH:D008568) association a(CHEBI:"glutamate(1-)") View Subject | View Object

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path(MESH:D013850) association a(MESH:D006624) View Subject | View Object

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path(MESH:D013850) association a(MESH:D019579) View Subject | View Object

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path(MESH:D013850) association a(CHEBI:"glutamate(1-)") View Subject | View Object

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Evidence 08de339322
JSON

In healthy individuals, the glutamatergic neurotransmission cycle begins in the mitochondria of hippocampal neurons, where the enzyme glutaminase catalyzes the conversion of glutamine to glutamate. Next, the vesicular glutamate transporter molecule mediates the packaging of these glutamate molecules into vesicles. Glutamate-containing vesicles are then released from the neuron, resulting in elevated synaptic concentrations of free glutamate, which can transmit neural signals by interacting with glutamatergic receptors on postsynaptic neurons

a(CHEBI:"glutamate(2-)") directlyIncreases bp(GO:"GO:0014047") View Subject | View Object

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Annotations
MeSH
Mitochondria
Cell Ontology (CL)
hippocampal neuron
MeSH
Hippocampus

bp(GO:"GO:0014047") increases bp(GO:"GO:0035249") View Subject | View Object

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Annotations
MeSH
Mitochondria
Cell Ontology (CL)
hippocampal neuron
MeSH
Hippocampus

act(p(HGNC:GLS), ma(cat)) directlyIncreases a(CHEBI:"glutamate(1-)") View Subject | View Object

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Annotations
MeSH
Mitochondria
Cell Ontology (CL)
hippocampal neuron
MeSH
Hippocampus

Evidence beb1c17331
JSON

First, the presence of elevated neurotransmitter levels in the synapse under resting conditions can be thought of as a constant 'background signal,' leading to chronic low-level activation of glutamatergic receptors on postsynaptic neurons and possibly neuronal death.

a(CHEBI:"glutamate(2-)") directlyIncreases act(p(MESH:D017470)) View Subject | View Object

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

bp(GO:"GO:0070997") association act(p(MESH:D017470)) View Subject | View Object

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

act(p(MESH:D017470)) association bp(GO:"GO:0070997") View Subject | View Object

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

Evidence 111ff0aac8
JSON

In individuals with normal cognitive functioning, Mg2+ blocks the passage of Ca2+ through the neuronal NMDA receptor calcium channel under resting conditions, but it is readily displaced when membrane depolarization occurs and synaptic glutamate concentrations are at peak levels (ie, when neuronal firing occurs).

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

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Evidence 4a35cd5f5c
JSON

Pyramidal neurons, which account for ~70% of all neurons in the neocortex, use glutamate as their primary neurotransmitter. Nonetheless, in addition to possessing glutamatergic receptors on their surface, these neurons often also possess cholinergic receptors, which are capable of receiving cholinergic inputs into the neocortex from the basal forebrain. The presence of these cholinergic receptors has been putatively linked to an important finding regarding the interaction between the cholinergic and glutamatergic neurotransmission systems. In particular, rodent studies have revealed that cholinesterase inhibitors (ChEIs) promote the release of glutamate from pyramidal neurons,16 with the proposed explanation being that ChEI administration leads to increased cortical ACh concentrations and, consequently, increased binding of ACh by cholinergic receptors on pyramidal neurons, thereby stimulating neuronal firing (ie, glutamate release).

a(CHEBI:acetylcholine) increases complex(a(CHEBI:acetylcholine), p(MESH:D011950)) View Subject | View Object

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Annotations
Cell Ontology (CL)
pyramidal neuron
MeSH
Neocortex

a(MESH:D002800) increases bp(GO:"GO:0014047") View Subject | View Object

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Annotations
Cell Ontology (CL)
pyramidal neuron
MeSH
Neocortex

a(MESH:D002800) increases a(CHEBI:acetylcholine) View Subject | View Object

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Annotations
Cell Ontology (CL)
pyramidal neuron
MeSH
Neocortex

a(MESH:D017966) association composite(p(MESH:D011950), p(MESH:D017470)) View Subject | View Object

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Annotations
Cell Ontology (CL)
pyramidal neuron
MeSH
Neocortex

complex(a(CHEBI:acetylcholine), p(MESH:D011950)) increases a(CHEBI:acetylcholine) View Subject | View Object

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Annotations
Cell Ontology (CL)
pyramidal neuron
MeSH
Neocortex

composite(p(MESH:D011950), p(MESH:D017470)) association a(MESH:D017966) View Subject | View Object

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Annotations
Cell Ontology (CL)
pyramidal neuron
MeSH
Neocortex

Evidence 9d0b7091f3
JSON

Synaptic glutamate concentration is promptly restored to normal levels, however, through the rapid uptake of unbound glutamate molecules by nearby glial cells, which subsequently convert these glutamate molecules to glutamine. The resulting glutamine molecules are then recycled to the neurons, and the cycle of glutamatergic signaling begins anew

a(CHEBI:glutamine) increases bp(GO:"GO:0006868") View Subject | View Object

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Cell Ontology (CL)
glial cell

bp(GO:"GO:0035249") increases bp(GO:"GO:0051935") View Subject | View Object

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Cell Ontology (CL)
glial cell

bp(GO:"GO:0051935") increases a(CHEBI:glutamine) View Subject | View Object

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Cell Ontology (CL)
glial cell

Evidence 3bd5fdba7d
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According to the proposed hypothesis, memantine has the ability to block the passage of Ca2+ through the calcium channel even when, as in Alzheimer's disease, resting synaptic glutamate levels are abnormally high, but it is still readily displaced at peak synaptic glutamate concentrations.13 In other words, the clinical efficacy of memantine appears to stem from its ability to prevent neuronal overactivity without also hindering normal neurotransmission.

a(CHEBI:memantine) decreases complex(a(CHEBI:"calcium(2+)"), p(GFAM:"Glutamate ionotropic receptor NMDA type subunits")) View Subject | View Object

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Disease Ontology (DO)
Alzheimer's disease

a(CHEBI:memantine) causesNoChange bp(MESH:D009435) View Subject | View Object

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Disease Ontology (DO)
Alzheimer's disease

Evidence 77df9e615e
JSON

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

bp(GO:"GO:0007271") association path(MESH:D003071) View Subject | View Object

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Annotations
Disease Ontology (DO)
Alzheimer's disease

bp(GO:"GO:0035249") association path(MESH:D003071) View Subject | View Object

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Annotations
Disease Ontology (DO)
Alzheimer's disease

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

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Annotations
Disease Ontology (DO)
Alzheimer's disease

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

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Annotations
Disease Ontology (DO)
Alzheimer's disease

path(MESH:D003071) association bp(GO:"GO:0035249") View Subject | View Object

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Annotations
Disease Ontology (DO)
Alzheimer's disease

path(MESH:D003071) association bp(GO:"GO:0007271") View Subject | View Object

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Annotations
Disease Ontology (DO)
Alzheimer's disease

Evidence 563a4215f2
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Glutamatergic and cholinergic abnormalities are strongly correlated with cognitive deterioration in Alzheimer's disease, and both types of abnormalities have been hypothesized to have a causative role in this deterioration. The two major classes of agents used to treat cognitive symptoms of Alzheimer's disease are ChEIs and NMDA receptor antagonists.

bp(GO:"GO:0007271") association path(MESH:D003071) View Subject | View Object

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Annotations
Disease Ontology (DO)
Alzheimer's disease

bp(GO:"GO:0035249") association path(MESH:D003071) View Subject | View Object

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Annotations
Disease Ontology (DO)
Alzheimer's disease

path(MESH:D003071) association bp(GO:"GO:0007271") View Subject | View Object

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Annotations
Disease Ontology (DO)
Alzheimer's disease

path(MESH:D003071) association bp(GO:"GO:0035249") View Subject | View Object

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Annotations
Disease Ontology (DO)
Alzheimer's disease

Evidence 42688ffe98
JSON

In fact, it has been demonstrated that decreasing levels of ACh synthesis are significantly correlated with increasing severity of dementia in patients with Alzheimer's disease (Table)

bp(GO:"GO:0008292") association path(MESH:D003704) View Subject | View Object

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Disease Ontology (DO)
Alzheimer's disease

path(MESH:D003704) association bp(GO:"GO:0008292") View Subject | View Object

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Annotations
Disease Ontology (DO)
Alzheimer's disease

Evidence 49cf2007f2
JSON

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)

bp(GO:"GO:0014047") increases bp(MESH:D017774) View Subject | View Object

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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

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

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

Evidence 3dcd90213b
JSON

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

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

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Annotations
Disease Ontology (DO)
Alzheimer's disease

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

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Annotations
Disease Ontology (DO)
Alzheimer's disease

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

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Annotations
Disease Ontology (DO)
Alzheimer's disease

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

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Annotations
Disease Ontology (DO)
Alzheimer's disease

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

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Disease Ontology (DO)
Alzheimer's disease

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

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Annotations
Disease Ontology (DO)
Alzheimer's disease

Evidence abe6555b2d
JSON

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.

bp(MESH:D017774) association path(MESH:D008568) View Subject | View Object

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Annotations
Cell Ontology (CL)
glial cell
MeSH
Frontal Lobe
MeSH
Temporal Lobe

bp(MESH:D017774) association path(MESH:D007858) View Subject | View Object

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Annotations
Cell Ontology (CL)
glial cell
MeSH
Frontal Lobe
MeSH
Temporal Lobe

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

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

path(MESH:D007858) association bp(MESH:D017774) View Subject | View Object

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

path(MESH:D008568) association bp(MESH:D017774) View Subject | View Object

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

Evidence 9baab7f8e1
JSON

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.

act(p(GFAM:"Glutamate ionotropic receptor NMDA type subunits")) decreases bp(MESH:D017774) View Subject | View Object

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

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

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

Evidence bb059614cb
JSON

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

act(p(HGNC:CHAT), ma(cat)) increases a(CHEBI:acetylcholine) View Subject | View Object

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

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

Evidence ef90d82787
JSON

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

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

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

Evidence 6aa42118f4
JSON

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.

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

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

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

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

Evidence e5beedbad7
JSON

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

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

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Evidence 5121135833
JSON

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

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

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

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

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