The goal of this project is to understand the cellular and molecular basis of beta-amyloid peptide (Abeta) toxicity. This peptide is deposited as insoluble amyloid aggregates in the senile plaques found in the brains of Alzheimer's Disease (AD) patients, and is believed to be central to the pathology of this disease. A novel AD model system will be employed in which of the intensely studied nematode worm, Caenorhabditis elegans, is engineered to express human Abeta peptide. These transgenic animals express high levels of the Abeta peptide, which rapidly leads to the formation of amyloid deposits and associated toxic effects. This model system will be used to investigate the relationships between Abeta structure, aggregation, and toxicity by the construction of transgenic animals expressing wild-type and variant Abeta containing single or multiple amino acid substitutions. These animals will be assayed for amyloid formation and known markers of Abeta toxicity, such as oxidative damage to proteins. Characterization of these animals will also include examination of the complete Abeta-dependent gene expression profile, assayed by mRNA hybridization to DNA microarrays that contain probes for the vast majority of C. elegans genes. The genetic accessibility of this model organism will also allow the identification of genes directly involved in Abeta toxicity, by the isolation and characterization of mutations that suppress the toxic effects of the Abeta peptide.
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