Affiliations: Department of Psychiatry, Washington University School
of Medicine, St. Louis, MO 63110, USA
Note: [] Corresponding author: J.W. Olney, Department of Psychiatry, Washington University School
of Medicine, 4940 Children's Place, St. Louis, MO 63110, USA. Tel.: +1 314
362 2476; Fax: +1 314 362 2099
Abstract: 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, consquent neurofibrillary tangle formation and cognitive
decline. We propose that certain pharmacological methodes which have been found
to protect against NRHypo-induced neurodegeneration in animal brain might be
useful treatments for AD.
