Novel Animal Models of Familial British, Danish and Alzheimer's Dementia

[unreadable] DESCRIPTION (provided by applicant): Alzheimer's disease (AD) pathogenesis is firmly associated with the processing of the transmembrane amyloid precursor protein (APP), as demonstrated by the fact that mutations in APP or in the enzymes responsible for its processing cause Familial Alzheimer's disease. Because of its biological and pathological importance, understanding how APP cleavage is controlled is of great relevance. Based on the analogy between APP and Notch signaling, we have postulated the existence of integral membrane proteins that can bind APP, regulating its processing. We have recently identified as a putative APP ligand BRI2, a protein found mutated in patients with Familial British and Danish Dementia (FBD and FDD), two diseases clinically and pathologically similar to Alzheimer's disease. Our preliminary data show that BRI2 inhibits APP processing and, in turn, Abeta production in cell lines. Moreover, BRI2 mutants, which cause FBD and FDD, are less potent inhibitors of APP processing. These findings suggest that BRI2 regulates and/or modifies AD pathogenesis and that BRI2 FBD and FDD mutants are ineffective inhibitors of Abeta generation in vivo. This last point hints to the possibility that dis-regulation of APP processing may participate in the pathogenesis of FDD and FBD. [unreadable] [unreadable] Here, we propose to generate animal models to test these hypotheses. The development of these animal models would provide unvialable tools for a better understanding the pathogenesis of Alzheimer's disease, and perhaps FDD and FBD, as well as a valuable system for the evaluation of novel therapeutic strategies directed toward these pathogenic processes. [unreadable] [unreadable] [unreadable]