The proposed projects utilize immunohistochemical, in situ hybridization and Western blot analysis to examine the distribution and density of specific glutamate receptor subtypes (protein and mRNA) within the entorhinal cortex and hippocampus of normal control patients and patients with Alzheimer's disease pathology. Although it has been recognized for decades that certain cell populations are more prone than others to develop AD pathology it is unclear the morphologic, biochemical and physiological features which distinguish these cells as well it is unknown the underlying mechanism which renders certain cell populations at risk in AD. It is our basic believe that glutamate mechanisms, although likely not the cause of AD, nevertheless contribute significantly to the neuronal degeneration observed in AD. Accordingly, we hypothesize that neuronal vulnerability may in part be defined by a cells specific response to glutamate as regulated through the expression of selected glutamate receptor subunits. Moreover, in AD the perturbation of specific glutamate receptor subunits, particularly those involved in the gating of Ca2+, may have profound effects on the cells ability to maintain normal intracellular homeostatic mechanisms which in turn may contribute significantly to the cell's viability. In addition, it is becoming recognized that the plasticity of inotropic non-NMDA receptors is dependent upon external stimuli. For example, the expression of nonNMDA receptor subunits are developmentally regulated and appear to change in pathologic conditions such as brain ischemia. Our preliminary data in AD also indicate marked plasticity of selected non-NMDA receptor subunits within specific brain regions. Accordingly, detailed information concerning the anatomical organization of specific glutamate receptor subtypes in the brains of control patients and in patients with AD may bear significantly on our understanding of the pathogenesis of AD and will provide the basis for rational pathology drug therapies specifically targeted at one or another glutamate receptor subtype.
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