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Glumate receptor dysfunction and Alzheimer's disease.
J W Olney1, D F Wozniak, N B Farber
1Department of Psychiatry, Washington University School of Medicine, St. Louis, MO 63110, USA. olneyj@psychiatry.wustl.edu
Restorative Neurology and Neuroscience
|April 3, 2003
Summary
Impaired N-methyl-D-aspartate (NMDA) receptor function may drive Alzheimer's disease (AD) pathophysiology through excitotoxicity and neurodegeneration. Treatments protecting against this NMDA receptor hypofunctional state could offer therapeutic benefits for AD.
Area of Science:
- Neuroscience
- Pathophysiology
- Pharmacology
Background:
- Alzheimer's disease (AD) pathophysiology is complex, involving neuronal dysfunction.
- The N-methyl-D-aspartate (NMDA) glutamate receptor system's role in AD is under investigation.
Purpose of the Study:
- To review the hypothesis linking impaired NMDA receptor function to Alzheimer's disease.
- To propose a two-stage model for NMDA receptor hypofunction in AD pathogenesis.
- To explore potential pharmacological treatments targeting this mechanism.
Main Methods:
- Review of existing literature and hypotheses.
- Proposal of a two-stage pathophysiological model for AD.
- Discussion of potential therapeutic strategies based on animal models.
Main Results:
- A two-stage process is proposed: initial excitotoxic injury leading to NMDA receptor hypofunction (NRHypo), followed by neurodegeneration and cognitive decline.
- Amyloidopathy, oxidative stress, and metabolic disturbances may prime neurons for excitotoxicity.
- NRHypo state may disinhibit neural circuits, causing widespread neurodegeneration and neurofibrillary tangle formation.
Conclusions:
- Impaired NMDA receptor function is a key hypothesis in understanding AD.
- The proposed NRHypo model offers a framework for AD pathophysiology.
- Pharmacological agents protecting against NRHypo-induced neurodegeneration may be potential AD treatments.