We have engineered a transgenic Caenorhabditis elegans model system that allows inducible expression of human beta amyloid peptide (Abeta1-42) in neuronal or muscle tissue. In both instances, Abeta accumulates intracellularly, forms amyloid, and results in cellular pathology. The goal of the proposed work is to understand the molecular and cellular basis of this toxicity, and to investigate how these processes might be involved in Alzheimer's disease pathology. The proposed project takes advantage of the experimental tools available in C. elegans, many of which are not available in other model systems. Specifically, we will use forward genetic screens to identify mutations that suppress Abeta toxicity, thereby identifying genes and gene products involved in transducing or combating this toxicity. The transgenic animals will also be used in microarray-based gene expression studies, allowing a molecular description of the initial cellular response to Abeta toxicity. The relationship between Abeta aggregation and toxicity will be investigated by the construction of additional transgenic lines expressing natural and engineered variant Abeta peptides. The role of specific genes and gene products in Abeta toxicity will be investigated using double-stranded RNA inhibition (RNAi) and Green Fluorescent Protein (GFP)-based transgenic reporter constructs.