Alzheimer's disease is characterized, among other abnormalities, by the presence of large numbers of amyloid-containing lesions known as """"""""plaques"""""""" in the brain. This proposal is based on the hypothesis that amyloid deposition has an important role in the pathogenesis of Alzheimer's disease. We plan to investigate this role using transgenic mice expressing human amyloid proteins and molecules that modulate amyloid expression in the brain. We propose that transgene-induced amyloid deposition in the brain, through constitutive overexpression of amyloid or of protease inhibitors (such as alpha/1-antichymotrypsin), or both, may provide a highly informative model to understand the mechanisms responsible for the development of Alzheimer-like lesions, and perhaps even a model for Alzheimer's disease itself. This working hypothesis will be tested in several strains of transgenic mice, most of which have already been generated and shown to develop cerebral amyloid deposits that are associated with ultrastructural abnormalities in the neuropil that include neuritic changes. The work will focus on a detailed analysis of the molecular composition, cytological features, spatial distribution and temporal course (pre- and postnatal, and throughout aging) of transgene product expression and deposition, and may associate lesions, at the light and electron microscopic level. We expect this work to provide a wealth of information on the mechanisms that lead to amyloid deposition in the brain, on whether such deposition has a deleterious effect on neural structure and on some important aspects of its molecular composition. This information will be helpful to assess several hotly debated hypotheses about the pathogenesis of Alzheimer's disease, will help characterize a novel model of Alzheimer-like lesions, and perhaps will also provide a new unifying mechanism to account for multiple probable causes of Alzheimer's disease (both genetic and environmental). Such knowledge will likely be helpful, beyond the term of this proposal, to formulate new strategies to try to prevent and perhaps alleviate some aspects of the neural degeneration that leads to Alzheimer's disease and related conditions.
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