BRI2 inhibits amyloid beta-peptide precursor protein processing by interfering with the docking of secretases to the substrate.

Genetic alterations of amyloid beta-peptide (Abeta) production caused by mutations in the Abeta precursor protein (APP) cause familial Alzheimer's disease (AD). Mutations in BRI2, a gene of undefined function, are linked to familial British and Danish dementias, which are pathologically and clinically similar to Alzheimer's disease. We report that BRI2 is a physiological suppressor of Abeta production. BRI2 restrict docking of gamma-secretase to APP and access of alpha- and beta-secretases to their cleavage APP sequences. Alterations of BRI2 by gene targeting or transgenic expression regulate Abeta levels and AD pathology in mouse models of AD. Competitive inhibition of APP processing by BRI2 may provide a new approach to AD therapy and prevention.