Glutamate receptor dysfunction and Alzheimer's disease

In this article we review the hypothesis that impaired function of the N-methyl-Daspartate (NMDA) glutamate receptor system may be an important mechanism for understanding the pathophysiology of Alzheimer's disease (AD). We propose a two stage process, the first involving amyloidopathy, oxidative stress 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 circuits, which leaves these circuits in an NMDA receptor hypofunctional (NRHypo) state. In the second stage this NRHypo state results in the disinhibition of a complicated neural circuitry that leads to widespread neurodegeneration in corticolimbic areas, consequent neurofibrillary tangle formation and cognitive decline. We propose that certain pharmacological methods which have been found to protect against NRHypo-induced neurodegeneration in animal brain might be useful treatments for AD.