One of the major mechanisms of cell death that has been implicated in several neurodegenerative disorders, including Alzheimer's disease, is glutamate-receptor mediated excitotoxicity. Until recently it was not feasible to delineate with precision the glutamate receptor subunit profile of identified neurons and circuits in the cerebral cortex. However, with the molecular characterization of the specific subunit proteins and the development of riboprobes and subunit specific antibodies, it is now feasible to develop detailed glutamate receptor profiles of both vulnerable and resistant neurons that are subunit-and family-specific that will delineate the degree to which certain glutamate receptor subunit molecules might be implicated in the differential vulnerability that is apparent in Alzheimer's disease. Within this context this project will be directed at the four major goals. 1) Screening of monoclonal antibodies that are directed against subunits of the non-NMDA(GluR1-7) and NMDA families of glutamate receptors for their effectiveness in immunohistochemical studies of human cortex. 2) These immunohistochemical probes, as well as riboprobes, will be used to analyze the regional, laminar and cellular distribution of specific glutamate receptor subunit proteins and related mRNAs in monkey and human neocortex and hippocampus. 3) Double labelling paradigms will be employed to determine the comprehensive glutamate receptor profile a well as correlations between the presence of certain glutamate receptor subunits and other neurochemical characteristics that have been correlated with either vulnerability or resistance to degeneration in Alzheimer's disease. These studies initially will concentrate on colocalization with cytoskeletal and Ca+2-binding proteins. 4) Alzheimer's disease related changes in the dendritic, cellular, laminar, or regional distribution of such subunit proteins and/or related mRNA's will be determined through comparison of immunohistochemical patterns in brains from Alzheimer's disease patients, elderly controls, and young controls. Through this combined analysis of normative human material, Alzheimer's disease tissue, and genetically manipulated mice it is hoped that we will be able to develop a precise glutamate receptor profile that can be linked to the differential vulnerability apparent in Alzheimer's disease and within this context develop quantitative data on shifts in the expression of specific subunits and related glutamate receptor families that might be causally related to the neurodegeneration of specific subsets of cortical neurons that occurs in Alzheimer's disease.
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