Interaction of the amyloid precursor protein with PTB domain-containing adaptors and their potential involvement in Alzheimer's disease

Fe65 is a brain-abundant protein with the modular structure of a typical adaptor, containing three protein-protein interaction domains. Fe65 and the related proteins Fe65L1 and Fe65L2 interact with the cytosolic domain of the Alzheimer's P-amyloid precursor protein (APP), a membrane protein, from which the P-amyloid peptide (AD), is generated. Ligands for the other Fe65 protein-protein interaction domains have also been identified. Fe65 proteins are not the unique ligands of the APP cytodomain; other adapters, such as X11alpha and Dab-1, bind APP in a fashion similar to Fe65. Since the interaction of either Fe65 or X11alpha or Dab-1 with APP seem to be mutually exclusive, it is believed that each adaptor is able to recruit at the membrane level large macromolecular complexes involved in different cellular activities, such as the intracellular trafficking of proteins and vesicles. The molecular characterization of this system of interacting proteins is believed to be important for the understanding of the molecular mechanisms leading to AD pathogenesis, since overexpression in cultured cells of either Fe65 or X11 causes opposite effects on APP processing and AD generation.