Accumulation of the neurotoxic Abeta peptide is a major contributing factor to Alzheimer's disease (AD). IDE is an enzyme that helps clear Ab. Therefore, enhancing IDE activity could improve Abeta clearance and slow AD progression. This study relies on biochemical and genetic approaches to investigate the enzymatic properties of IDE as they pertain to Abeta degradation. Our genetic approach, in particular, is unique to our research program. Our system has inherent time and cost advantages over others for the study of IDE and represents the only high-throughput genetic system for the study of IDE. In this project, we have two main aims. First, we will use chemical screening methods in conjunction with biochemical approaches to identify activators and inhibitors of IDE. These agents will represent important new tools for understanding the function of IDE, with activators being potential lead compounds for enhancing Abeta clearance via drug-based therapeutic strategies. Second, we will characterize existing hyperactive alleles of IDE and take advantage of molecular modeling and/or our genetic system to isolate novel IDE alleles having improved proteolytic activity. We expect that these hyperactive alleles could be used to enhance Abeta clearance via enzyme-based therapeutic strategies. Our unique research approach will provide new and significant insight about IDE function and activity modulators. We expect that this knowledge will help us and others direct future efforts aimed at enhancing Abeta clearance as part of new therapeutic approaches for AD.