Previous findings from the PI's laboratory demonstrate: 1) that classic markers of the immune system, including IL-2 receptors, NK, HLA-DP, HLA-DQ, and HLA-DR, are profusely expressed in human brain; 2) that HLA-DR expression increases with age and Alzheimer's disease (AD); 3) that HLA-DR immunopositive cells, including putative astrocytes, microglia, and macrophages, co-localize with the senile plaques of AD; 4) that such cells ingest and may process the abnormal protein amyloid in AD; 5) that such cells bear surface receptors necessary for presentation of abnormal proteins as antigens to activated T cells; 6) that activated T cells can be found in the AD brain; and 7) that the apposition of presumptive T cells with brain glia, necessary for antigen presentation, can be demonstrated. The present proposal embodies an effort to demonstrate a specific immune-related action of brain glia and macrophages as one of the primary determinants of the widespread neural degeneration characteristic of AD. This is both a new and an old idea-old in the sense that brain glia and macrophages have long been presumed to be involved in clearing away the pathologic debris of AD, but new in the belief that they may be doing so in an immune context. If successful, the proposed experiments will help demonstrate a novel pathogenetic mechanism in AD, and could have important implications as well for several other neurologic disorders (e.g., multiple sclerosis) which already have clear neuoimmune correlates.
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