Identifying regulators of APP gamma secretase

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DESCRIPTION (provided by applicant): Alzheimer's disease (AD) is a neurodegenerative disorder of the brain and the most common form of senile dementia. The central pathological event leading to AD is thought to be the accumulation of amyloid plaques consisting primarily of a toxic peptide known as amyloid beta peptide (A-beta) in the brain. A-beta is derived from APP by proteolytic processing via the action of two proteases, one of which is gamma secretase. The aberrant action of gamma secretase function underlies the most common early onset familial AD. Gamma secretase resides in a large multi-protein complex with four essential components: presenilin, nicastrin, aph-1 and pen-2. Identifying mechanisms by which gamma secretase activity is regulated should lead to an increased understanding of AD pathogenesis and may provide insight in developing new diagnostic tools and therapeutic targets. Drosophila has been used with great success as a molecular genetic tool to identify new genes and study essential biological processes. In Drosophila, the gamma secretase activity and its four essential components are functionally conserved. Thus regulators of gamma secretase identified in Drosophila are likely to be functionally conserved. We have developed a reporter system in the living Drosophila eye that allows us to visualize the endogenous level of gamma secretase activity. Using these flies as a genetic background, we have carried out genetic screens and have identified several candidates to be characterized further. The specific aims of this proposal are: 1. Carry out loss-of-function screens, clone candidate genes and characterize their sites of function. 2. Characterize gain-of-function modifiers of gamma-secretase activity. 3. Determine how the candidate gene interacts with genes encoding components of gamma-secretase complex, aph-1, pen-2, nicastrin and presenilin