Glutamate receptor dysfunction and Alzheimer's disease

In this article we review the hypothesis that impaired function of the N-me thyl-Daspartate (NMDA) glutamate receptor system may be an important mechan ism for understanding the pathophysiology of Alzheimer's disease (AD). We p ropose a two stage process, the first involving amyloidopathy, oxidative st ress and/or energy metabolic disturbances promoting neuronal sensitivity to glutamate-induced excitotoxic injury to an extent that even normal amounts of Glu become excitotoxic. As a consequence, NMDA receptor-bearing neurons (and their NMDA receptors) are deleted from critical corticolimbic brain c ircuits, which leaves these circuits in an NMDA receptor hypofunctional (NR Hypo) state. In the second stage this NRHypo state results in the disinhibi tion of a complicated neural circuitry that leads to widespread neurodegene ration in corticolimbic areas, consequent neurofibrillary tangle formation and cognitive decline. We propose that certain pharmacological methods whic h have been found to protect against NRHypo-induced neurodegeneration in an imal brain might be useful treatments for AD.