Glutamate-mediated excitotoxicity and neurodegeneration in Alzheimer?s disease
Abstract
Alzheimer's disease (AD) is the most common form of dementia, accounting for 60-70% of cases in subjects over 65 years of age. Several postulates have been put forward that relate AD neuropathology to intellectual and functional impairment. These range from free-radical-induced damage, through cholinergic dysfunction, to beta-amyloid-induced toxicity. However, therapeutic strategies aimed at improving the cognitive symptoms of patients via choline supplementation, cholinergic stimulation or beta-amyloid vaccination, have largely failed. A growing body of evidence suggests that perturbations in systems using the excitatory amino acid L-glutamate (L-Glu) may underlie the pathogenic mechanisms of (e.g.) hypoxia-ischemia, epilepsy, and chronic neurodegenerative disorders such as Huntington's disease and AD. Almost all neurons in the CNS carry the N-methyl-D-aspartate (NMDA) subtype of ionotropic L-glutamate receptors, which can mediate post-synaptic Ca2+ influx. Excitotoxicity resulting from excessive activation of NMDA receptors may enhance the localized vulnerability of neurons in a manner consistent with AD neuropathology, as a consequence of an altered regional distribution of NMDA receptor subtypes. This review discusses mechanisms for the involvement of the NMDA receptor complex and its interaction with polyamines in the pathogenesis of AD. NMDA receptor antagonists have potential for the therapeutic amelioration of AD.
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This could lead to synaptic loss due to excitotoxicity and reduced synaptogenesis due to the destabilization of nascent synapses, which would result in a net loss of synapses during disease progression.
“This could lead to synaptic loss due to excitotoxicity (6, 33, 34) and reduced synaptogenesis due to the destabilization of nascent synapses (16, 17), which would result in a net loss of synapses during disease progression.”
From Single-nucleus transcriptome analysis reveals dysregulation of angiogenic endothelial cells and neuroprotective glia in Alzheimer’s disease (2020) · cites this paper as [6]
Impaired recycling of neurotransmitters, especially glutamate, results in excitotoxicity and leads to neuronal death.
“Indeed, impaired recycling of neurotransmitters, especially glutamate, results in excitotoxicity and leads to neuronal death (6).”
From Single-nucleus transcriptome analysis reveals dysregulation of angiogenic endothelial cells and neuroprotective glia in Alzheimer’s disease (2020) · cites this paper as [6]
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- Authors
- HYND, M.
- Affiliations
- The University of Queensland (AU)
- Corresponding author
- HYND, M
- Venue
- Neurochemistry International
- Publisher
- Elsevier BV
- Published
- 2004-10
- Volume
- 45
- Issue
- 5
- Pages
- 583-595
- ISSN
- 0197-0186 (ISSN-L)
- OpenAlex
- W2166070786
- Cited by
- 938
- References
- 7
- Citations by year
- 2026: 20 · 2025: 46 · 2024: 35 · 2023: 50 · 2022: 59 · 2021: 65 · 2020: 57 · 2019: 44 · 2018: 56 · 2017: 52 · 2016: 35 · 2015: 28 · 2014: 46 · 2013: 46 · 2012: 49
- FWCI
- 21.58
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Neurochemistry International (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- Alzheimer's disease, excitotoxicity, glutamate, NMDA receptor, neurodegeneration, polyamines, NMDA receptor antagonists, calcium influx, amyloid-beta, cholinergic dysfunction, glutamate receptor subtypes
- MeSH terms
- Alzheimer Disease, Animals, Humans, Nerve Degeneration, Synaptic Transmission, Biogenic Polyamines, Receptors, N-Methyl-D-Aspartate, Glutamic Acid, Excitatory Amino Acids
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