Senile plaques (SP) are essential to the histopathological diagnosis of Alzheimer's disease (AD), but are also found in the brains of many nondemented elderly humans. Brains of cognitively normal old people with numerous SP have been operationally defined as pathological aging (PA). Senile plaques are also common in the second leading cause of primary degenerative dementia, diffuse Lewy body disease (DLBD), which shares histopathological features with Parkinson's disease, but is usually clinically indistinguishable from AD. Our previous studies demonstrated similarities between SP in PA and DLBD, but differences from SP in AD. With this in mind, it is our goal to study SP pathogenesis with the underlying hypothesis that fundamental qualitative differences exist between lesions of PA and DLBD compared to AD. We further postulate that SP evolve through a process whereby initially nonfibrillar preamyloid deposits undergo fibrillogenesis promoted by binding of amyloid to heparin sulfate proteoglycans and other amyloid-associated proteins, including apo-E. The resulting long-lived amyloid deposits are progressively glycated, which then promotes reaction of glia (microglia and astrocytes) to the amyloid deposits and their subsequent activation. The ensuing inflammatory-like reaction leads to production of substances that induce additional amyloid fibrillogenesis and local neuritic dystrophy. To further elucidate the pathogenesis of SP, we propose qualitative and quantitative studies with three major specific aims using post-mortem brain tissue and cultured human brain cells. 1. To study qualitative morphological features of SP in AD, PA and DLBD using simultaneous fluorescent histochemical and multiple antibody immunolabeling techniques to determine the relationships of amyloid and amyloid-associated proteins (especially apo-E) to advanced glycation end- products (AGE), markers of glial activation, and markers of cytoskeletal pathology. 2. To determine if there are quantitative structural differences in the brains of AD, PA and DLBD using biochemical and immunochemical methods to assess apo-E, APP metabolites and protein glycation, and to determine if similar proteins are glycated in these brains. 3. To determine if interaction of AGE-proteins with cultured microglia and astrocytes leads to morphological features of activation, production of cytokines and glutamate and to proliferation. We admit that the processes we are studying are not the initial steps in SP formation, but we firmly believe that the later stages of the disease process are as significant as the earlier steps that have been the focus of most other laboratories. If in fact, understanding processes in these later steps of SP pathogenesis suggest points for therapeutic intervention, then they will more than justify their expense.
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