Regulation of the Physiological Function and Metabolism of AβPP by AβPP Binding Proteins

Amyloid-beta protein precursor (A beta PP) is a receptor-like, type-I membrane protein that plays a central role in the pathogenesis of Alzheimer's disease. The cytoplasmic domain of A beta PP is important for the metabolism and physiological functions of A beta PP and contains a GYENPTY motif that interacts with proteins that contain a phosphotyrosine binding (PTB) domain such as X11/Mint, FE65, and the JIP family of proteins. X11 and X11-like proteins are neuronal adaptor proteins involved in presynaptic function and the intracellular trafficking of proteins. Recent studies in X11s knockout mice confirmed findings from in vitro studies that X11 proteins affect A beta PP metabolism and the generation of amyloid-beta peptide. FE65 proteins are involved in transactivation in coordination with the intracellular domain fragment of A beta PP, and/or in cellular responses to DNA damage. Neurodevelopmental defects observed in FE65s double knockout mice suggest that FE65 proteins cooperate with A beta PP to play a role in neuronal cytoskeletal regulation. c-Jun N-terminal kinase (JNK) interacting protein-1 (JIP-1), a scaffolding protein for the JNK kinase cascade, has been suggested to mediate the intracellular trafficking of A beta PP by molecular motor kinesin-1. This article reviews some of the recent findings regarding the regulation of physiological function and metabolism of A beta PP by A beta PP binding proteins.