Thus far, five genes and their protein products have been implicated in the pathogenesis of Alzheimer's disease--APP (AD1), apoE (AD2), antichymotrypsin (ACT; putatively AD5), and the recently identified genes S182 (AD3) and its relative STM2 (AD4). The localization of the products of three of these genes A-beta( (from APP), ACT (by the applicant), and apoE (by others)--in the Alzheimer amyloid plaques provided the first evidence that their interaction might be essential for the development of these neuropathological lesions. The applicants have confirmed this prediction by showing that ACT and apoE4 strongly promote the polymerization of A-beta into amyloid filaments in vitro, which are toxic to human cortical neurons in culture. Furthermore, they have shown that activated microglial cells in the affected area of the Alzheimer brain express IL-1, that IL-1 is produced in vitro by cultured microglia from only these regions of normal brain, and that this IL-1 binds to the IL-1 receptor on astrocytes to induce them to synthesize the amyloid promoting factor ACT. These results reinforce our growing conviction that a glial-based inflammation cascade plays an important role in Alzheimer's disease pathogenesis. In the coming years, the applicants plan to use two experimental systems to further delineate the pathogenic pathway in Alzheimer's disease and to understand the role that changes in gene expression and protein localization play in this pathway. Specifically, they will use cultures of human neurons, astrocytes, and microglial cells to study the expression of the five known Alzheimer-related genes. They will focus on understanding how lymphokines, particularly IL-1, control the expression of these proteins, and the identification the basis of the region-specific differences in IL-1 production that appears to underlie the region-specific production of amyloid in Alzheimer's disease. They also plan to use these culture systems to investigate the effect of A-beta peptides and their macromolecular conformers on IL-1, apoE, and ACT expression in target glial cells. Finally, they plan to determine whether, as predicted, the novel ACT-A polymorphism associated with Alzheimer's disease increases the production of this amyloid-promoting factor. The second general approach is to use immunocytochemistry at the light and electron microscope levels to localize the protein products of the five Alzheimer's disease-related genes. They plan to focus particularly on the synapse, where three of these proteins (APP, ACT, and apoE) have already been localized, and which ours and others work indicates may be the birthplace of the amyloid deposits in the Alzheimer brain.
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