Adaptor protein interactions: modulators of amyloid precursor protein metabolism and Alzheimer's disease risk?

The cytoplasmic C-terminus of APP plays critical roles in its cellular trafficking and delivery to proteases. Adaptor proteins with phosphotyrosine-binding (PTB) domains, including those in the X11, Fe65, and c-Jun N-terminal kinase (JNK)-interacting protein (JIP) families, bind specifically to the absolutely conserved -YENPTY- motif in the APP C-terminus to regulate its trafficking and processing. Compounds that modulate APP-adaptor protein interactions may inhibit Abeta generation by specifically targeting the substrate (APP) instead of the enzyme (beta- or gamma-secretase). Genetic polymorphisms in (or near) adaptor proteins may influence risk of sporadic AD by interacting with APP in vivo to modulate its trafficking and processing to Abeta.