Glutamate transmission and toxicity in alzheimer's disease

Abstract

1. Despite intensive research, the cause of Alzheimer's disease is unknown. 2. Glutamate is the major excitatory transmitter of the cerebral cortex and hippocampus and it appears to have an important role in learning and memory. In addition to its transmitter function, glutamate is a neurotoxin which has been implicated in the pathogenesis of a variety of neurodegenerative disorders. 3. Glutamate toxicity may play a role in the pathogenesis of Alzheimer's disease. 4. Disruption of glutamatergic neurotransmission may account, in part, for the learning and memory deficits of Alzheimer's disease. 5. Labeling of the glutamate receptor complex may allow in vivo diagnosis by positron emission tomography. 6. Glutamate receptor ligands may provide a means of therapeutic intervention in Alzheimer's disease.

Imaging Neuroinflammation in Alzheimer's Disease with Radiolabeled Arachidonic Acid and PET

“…β-amyloid peptide in the AD brain also can provoke glutamate-induced excitotoxicity and well as PLA 2 activation (9, 10). Consistent with this scenario, the AD brain demonstrates increased cytokine levels (3), increased expression of both cPLA 2 and sPLA 2 , increased concentrations of inflammatory metabolites of AA (5, 11, 12), and increased glutamatergic markers and different forms of accumulated β-amyloid (9, 10, 13). Additionally, concentrations of isoprostane and isofuran metabolites of AA are elevated in cerebrospinal fluid (CSF) from AD patients (14).…”

Imaging Neuroinflammation in Alzheimer's Disease with Radiolabeled Arachidonic Acid and PET

“…β-amyloid peptide in the AD brain also can provoke glutamate-induced excitotoxicity and well as PLA 2 activation (9, 10). Consistent with this scenario, the AD brain demonstrates increased cytokine levels (3), increased expression of both cPLA 2 and sPLA 2 , increased concentrations of inflammatory metabolites of AA (5, 11, 12), and increased glutamatergic markers and different forms of accumulated β-amyloid (9, 10, 13). Additionally, concentrations of isoprostane and isofuran metabolites of AA are elevated in cerebrospinal fluid (CSF) from AD patients (14).…”

Paradoxical Upregulation of Glutamatergic Presynaptic Boutons during Mild Cognitive Impairment

“…Moreover, given that LTP is a key factor in memory and learning, the very functions affected by AD (Greenamyre et al, 1988), our data are highly relevant. In addition to the potential benefit of increasing transmission probability, it must also be noted that elevated levels of extracellular glutamate might also increase excitotoxicity [an event with established links to the cognitive impairment and neuronal death visible in AD (Greenamyre et al, 1988)] or activate extrasynaptic prodeath NMDA receptors (for review, see Hardingham and Bading, 2003), potentially contributing to the subsequent depletion in terminal numbers seen with progression to AD. In short, our report illustrates an important and hitherto underappreciated involvement of the cortical glutamatergic terminals in the AD pathology.…”

AI-Powered Mice Behavior Tracking and Its Application for Neuronal Manifold Analysis Based on Hippocampal Ensemble Activity in an Alzheimer’s Disease Mice Model

“…Altered hippocampal neuron functioning in Alzheimer’s disease mouse models is well established [ 59 , 60 , 61 , 62 ]. The accumulation of toxic Aβ-amyloid plaques plays a critical role in disrupting neuronal excitability and impairing neuron-to-neuron communication [ 32 , 63 , 64 ], primarily due to the extensive loss of spine apparatus function [ 65 , 66 , 67 , 68 ].…”

Imaging Neuroinflammation in Alzheimer's Disease with Radiolabeled Arachidonic Acid and PET

“…β-amyloid peptide in the AD brain also can provoke glutamate-induced excitotoxicity and well as PLA 2 activation (9, 10). Consistent with this scenario, the AD brain demonstrates increased cytokine levels (3), increased expression of both cPLA 2 and sPLA 2 , increased concentrations of inflammatory metabolites of AA (5, 11, 12), and increased glutamatergic markers and different forms of accumulated β-amyloid (9, 10, 13). Additionally, concentrations of isoprostane and isofuran metabolites of AA are elevated in cerebrospinal fluid (CSF) from AD patients (14).…”

Paradoxical Upregulation of Glutamatergic Presynaptic Boutons during Mild Cognitive Impairment

“…Moreover, given that LTP is a key factor in memory and learning, the very functions affected by AD (Greenamyre et al, 1988), our data are highly relevant. In addition to the potential benefit of increasing transmission probability, it must also be noted that elevated levels of extracellular glutamate might also increase excitotoxicity [an event with established links to the cognitive impairment and neuronal death visible in AD (Greenamyre et al, 1988)] or activate extrasynaptic prodeath NMDA receptors (for review, see Hardingham and Bading, 2003), potentially contributing to the subsequent depletion in terminal numbers seen with progression to AD. In short, our report illustrates an important and hitherto underappreciated involvement of the cortical glutamatergic terminals in the AD pathology.…”

AI-Powered Mice Behavior Tracking and Its Application for Neuronal Manifold Analysis Based on Hippocampal Ensemble Activity in an Alzheimer’s Disease Mice Model

“…Altered hippocampal neuron functioning in Alzheimer’s disease mouse models is well established [ 59 , 60 , 61 , 62 ]. The accumulation of toxic Aβ-amyloid plaques plays a critical role in disrupting neuronal excitability and impairing neuron-to-neuron communication [ 32 , 63 , 64 ], primarily due to the extensive loss of spine apparatus function [ 65 , 66 , 67 , 68 ].…”

Imaging Neuroinflammation in Alzheimer's Disease with Radiolabeled Arachidonic Acid and PET

“…β-amyloid peptide in the AD brain also can provoke glutamate-induced excitotoxicity and well as PLA 2 activation (9, 10). Consistent with this scenario, the AD brain demonstrates increased cytokine levels (3), increased expression of both cPLA 2 and sPLA 2 , increased concentrations of inflammatory metabolites of AA (5, 11, 12), and increased glutamatergic markers and different forms of accumulated β-amyloid (9, 10, 13). Additionally, concentrations of isoprostane and isofuran metabolites of AA are elevated in cerebrospinal fluid (CSF) from AD patients (14).…”

Paradoxical Upregulation of Glutamatergic Presynaptic Boutons during Mild Cognitive Impairment

“…Moreover, given that LTP is a key factor in memory and learning, the very functions affected by AD (Greenamyre et al, 1988), our data are highly relevant. In addition to the potential benefit of increasing transmission probability, it must also be noted that elevated levels of extracellular glutamate might also increase excitotoxicity [an event with established links to the cognitive impairment and neuronal death visible in AD (Greenamyre et al, 1988)] or activate extrasynaptic prodeath NMDA receptors (for review, see Hardingham and Bading, 2003), potentially contributing to the subsequent depletion in terminal numbers seen with progression to AD. In short, our report illustrates an important and hitherto underappreciated involvement of the cortical glutamatergic terminals in the AD pathology.…”

AI-Powered Mice Behavior Tracking and Its Application for Neuronal Manifold Analysis Based on Hippocampal Ensemble Activity in an Alzheimer’s Disease Mice Model

“…Altered hippocampal neuron functioning in Alzheimer’s disease mouse models is well established [ 59 , 60 , 61 , 62 ]. The accumulation of toxic Aβ-amyloid plaques plays a critical role in disrupting neuronal excitability and impairing neuron-to-neuron communication [ 32 , 63 , 64 ], primarily due to the extensive loss of spine apparatus function [ 65 , 66 , 67 , 68 ].…”