Project Summary Alzheimer’s disease (AD) remains the major cause of dementia and is a dreaded and dreadful disease. Genetic causes of early-onset AD have been the guiding lights in identifying and elucidating the key molecular players in this disease. Generation of abnormal proteins called Amyloid –ß (Aß) and tau are key pathological molecules in neurofibrillary tangles, themselves the hallmark of this disease. There is continuous generation of Aß and tau in brains throughout life, but patients with AD have a defect in their brain’s ability to clear these, accumulating them in the neurofibrillary tangles. Identifying and characterizing the transporters that help clear these proteins from the brain via the blood-brain barrier is therefore an important area of research. We have discovered a new pathway for Aß to be eliminated from the brain; we have very strong preliminary data that Abcg4 is one of these transporters. We hypothesize that the ATP-binding cassette homodimer G4 (Abcg4) is a bona fide exporter of Amyloid ß-peptide at the blood-brain barrier, and may play a role on the pathogenesis of Alzheimer’s disease. This proposal will test whether this first step can be verified in a mouse model of Abcg4 knockout, using a validated AD mouse model. Additionally, desmosterol, an endogenous sterol from the cholesterol biosynthesis pathway was a modulator of Aß secretion in vitro and this effect was dependent upon Abcg4 function. This work may allow us to link the cholesterol pathways to the AD pathways and may lead to greater insight into the pathophysiology of AD. If we can support our hypothesis, this will allow us to invest greater time, effort and funding into developing methods to enhance Aß export through development of novel therapies.