Affiliations: [a] Creative Research Institution Sousei, Hokkaido University, Kita-ku, Sapporo, Japan | [b] Laboratory of Neuronal Cell Biology, Graduate School of Pharmaceutical Sciences, Hokkaido University, Kita-ku, Sapporo, Japan | [c] Laboratory of Neuroscience, Graduate School of Pharmaceutical Sciences, Hokkaido University, Kita-ku, Sapporo, Japan | Department of Psychiatry and Human Behavior, University of Mississippi Medical Center, Jackson, MS, USA
Correspondence:
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Corresponding authors: Toshiharu Suzuki, Laboratory of Neuroscience, Graduate School of Pharmaceutical Sciences, Hokkaido University, Kita12-Nishi6, Kita-ku, Sapporo 060-0812, Japan. Tel.: +81 11 706 3250; Fax: +81 11 706 4991; E-mail: [email protected] or Hidenori Taru, Creative Research Institution Sousei, Hokkaido University, Kita21-Nishi10, Kita-Ku, Sapporo 001-0021, Japan. Tel.: +81 11 706 9213; Fax: +81 11 706 9238; E-mail: [email protected].
Abstract: Amyloid-β protein precursor (AβPP) is a receptor-like, type-I membrane protein that plays a central role in the pathogenesis of Alzheimer's disease. The cytoplasmic domain of AβPP is important for the metabolism and physiological functions of AβPP 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 AβPP metabolism and the generation of amyloid-β peptide. FE65 proteins are involved in transactivation in coordination with the intracellular domain fragment of AβPP, and/or in cellular responses to DNA damage. Neurodevelopmental defects observed in FE65s double knockout mice suggest that FE65 proteins cooperate with AβPP 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 AβPP by molecular motor kinesin-1. This article reviews some of the recent findings regarding the regulation of physiological function and metabolism of AβPP by AβPP binding proteins.
Keywords: Alzheimer's disease, amyloid-β protein precursor (AβPP), binding, metabolism
