Excitotoxic neurodegeneration in Alzheimer disease. New hypothesis and new therapeutic strategies - PubMed (original) (raw)
Review
Excitotoxic neurodegeneration in Alzheimer disease. New hypothesis and new therapeutic strategies
J W Olney et al. Arch Neurol. 1997 Oct.
Abstract
Excessive activation of N-methyl D-aspartate (NMDA) receptors by endogenous glutamate (Glu) causes excitotoxic neuronal degeneration in acute central nervous system injury syndromes such as stroke and trauma. Early attempts to link NMDA receptor hyperactivity (NRHyper) to Alzheimer disease (AD) were stymied by evidence in 3 separate species (mice, rats, and monkeys) that, with advancing age, the NMDA receptor system becomes markedly hypoactive. While this would seem to argue against a role for NMDA receptors in AD, we have recently found in animal studies that, when the NMDA receptor system is rendered markedly hypoactive, a disinhibition syndrome is triggered in which low-grade chronic excitotoxic activity (fueled by acetylcholine and Glu) is unleashed that can cause a widespread pattern of neuronal degeneration resembling that seen in AD. Therefore, we postulate that NMDA receptor hypoactivity (NRHypo) associated with advancing age may have an important contributory role in AD and that the main difference between the aging AD brain and the aging "normal" brain is that a heavier burden of certain adjunctive risk factors may be present in the AD brain that promote the NRHypo state and increase the likelihood that widespread neurodegeneration will occur.
Similar articles
- Does impairment of energy metabolism result in excitotoxic neuronal death in neurodegenerative illnesses?
Beal MF. Beal MF. Ann Neurol. 1992 Feb;31(2):119-30. doi: 10.1002/ana.410310202. Ann Neurol. 1992. PMID: 1349466 Review. - Excitotoxin-mediated neuron death in youth and old age.
Olney JW. Olney JW. Prog Brain Res. 1990;86:37-51. doi: 10.1016/s0079-6123(08)63165-9. Prog Brain Res. 1990. PMID: 1982368 Review. - Dopamine receptor activation reveals a novel, kynurenate-sensitive component of striatal N-methyl-D-aspartate neurotoxicity.
Poeggeler B, Rassoulpour A, Wu HQ, Guidetti P, Roberts RC, Schwarcz R. Poeggeler B, et al. Neuroscience. 2007 Aug 10;148(1):188-97. doi: 10.1016/j.neuroscience.2007.05.033. Epub 2007 Jul 16. Neuroscience. 2007. PMID: 17629627 Free PMC article. - Glutamate-mediated excitotoxicity and neurodegeneration in Alzheimer's disease.
Hynd MR, Scott HL, Dodd PR. Hynd MR, et al. Neurochem Int. 2004 Oct;45(5):583-95. doi: 10.1016/j.neuint.2004.03.007. Neurochem Int. 2004. PMID: 15234100 Review. - Glumate receptor dysfunction and Alzheimer's disease.
Olney JW, Wozniak DF, Farber NB. Olney JW, et al. Restor Neurol Neurosci. 1998;13(1-2):75-83. Restor Neurol Neurosci. 1998. PMID: 12671289
Cited by
- Review on anti-alzheimer drug development: approaches, challenges and perspectives.
Abdallah AE. Abdallah AE. RSC Adv. 2024 Apr 5;14(16):11057-11088. doi: 10.1039/d3ra08333k. eCollection 2024 Apr 3. RSC Adv. 2024. PMID: 38586442 Free PMC article. Review. - Sexual Dimorphism, Altered Hippocampal Glutamatergic Neurotransmission and Cognitive Impairment in APP Knock-In Mice.
Findley CA, McFadden SA, Hill T, Peck MR, Quinn K, Hascup KN, Hascup ER. Findley CA, et al. bioRxiv [Preprint]. 2024 Jun 14:2023.12.05.570100. doi: 10.1101/2023.12.05.570100. bioRxiv. 2024. PMID: 38106074 Free PMC article. Preprint. - Biochemical and Molecular Pathways in Neurodegenerative Diseases: An Integrated View.
Sanghai N, Tranmer GK. Sanghai N, et al. Cells. 2023 Sep 20;12(18):2318. doi: 10.3390/cells12182318. Cells. 2023. PMID: 37759540 Free PMC article. Review. - Extrasynaptic NMDA receptors in acute and chronic excitotoxicity: implications for preventive treatments of ischemic stroke and late-onset Alzheimer's disease.
Yu SP, Jiang MQ, Shim SS, Pourkhodadad S, Wei L. Yu SP, et al. Mol Neurodegener. 2023 Jul 3;18(1):43. doi: 10.1186/s13024-023-00636-1. Mol Neurodegener. 2023. PMID: 37400870 Free PMC article. Review. - Prodromal Glutamatergic Modulation with Riluzole Impacts Glucose Homeostasis and Spatial Cognition in Alzheimer's Disease Mice.
Findley CA, McFadden SA, Cox MF, Sime LN, Peck MR, Quinn K, Bartke A, Hascup KN, Hascup ER. Findley CA, et al. J Alzheimers Dis. 2023;94(1):371-392. doi: 10.3233/JAD-221245. J Alzheimers Dis. 2023. PMID: 37248899 Free PMC article.
Publication types
MeSH terms
Substances
LinkOut - more resources
Full Text Sources
Other Literature Sources
Medical