Inhibition of BACE1 in amyloidosis mouse

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DESCRIPTION (provided by applicant): One of the hallmarks of Alzheimer's Disease (AD) pathology is the presence of neuritic plaques in the brains of affected individuals. These plaques are made up of extracellular deposits of amyloid beta peptide (Abeta) surrounded by dystrophic neurites, reactive astrocytes, and microglia. The Abeta peptide is derived from the human amyloid precursor protein (APP) by the activities of two secretases, beta-site APP cleaving enzyme 1 (BACE1) and gamma (a complex of proteins), which sequentially cleave the precursor. This proposal is built upon the intriguing observation that deletion of BACE1, the principal beta secretase in neurons, completely prevents Abeta deposition in a mouse model of Abeta amyloidosis. A critical question, however, remains: Is Abeta-mediated pathology reversible by inhibiting the activity of BACE1? This proposal tests the hypothesis that inhibiting BACE1 expression will ameliorate the development and evolution of Abeta-mediated pathology in this mouse model. The proposed studies are designed to test this hypothesis by two different experimental approaches: RNA interference (RNAi) to silence BACE1 (AIM 1); and inducible knock out of BACE1 (AIM 2). The studies will provide an important validation of BACE1 as a therapeutic target for AD.