Maturation of BRI2 generates a specific inhibitor that reduces APP processing at the plasma memebrane and in endocytic vesicles

Processing of the amyloid-beta (A beta) precursor protein (APP) has been extensively studied since it leads to production of A beta peptides. Toxic forms of A beta aggregates are considered the cause of Alzheimer's disease (AD). on the other end, BRI2 is implicated in APP processing and A beta production. We have investigated the precise mechanism by which BRI2 modulates APP cleavages and have found that BRI2 forms a mature BRI2 polypeptide that is transported to the plasma membrane and endosomes where it interacts with mature APP. Notably, immature forms of APP and BRI2 fail to interact. Mature BRI2 inhibits APP processing by alpha-, beta- and gamma-secretases on the plasma membrane and in endocytic compartments. Thus, BRI2 is a specific inhibitor that reduces secretases' access to APP in the intracellular compartments where APP is normally processed. (C) 2009 Published by Elsevier Inc.