Intracellular Trafficking of the Amyloid beta-Protein Precursor (APP) Regulated by Novel Function of X11-Like

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概要

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• Background: Amyloid beta (A beta), a causative peptide of Alzheimer's disease, is generated by intracellular metabolism of amyloid beta-protein precursor (APP). In general, mature APP (mAPP, N- and O-glycosylated form) is subject to successive cleavages by alpha- or beta-, and gamma-secretases in the late protein secretory pathway and/or at plasma membrane, while immature APP (imAPP, N-glycosylated form) locates in the early secretory pathway such as endoplasmic reticulum or cis-Golgi, in which imAPP is not subject to metabolic cleavages. X11-like (X11L) is a neural adaptor protein composed of a phosphotyrosine-binding (PTB) and two C-terminal PDZ domains. X11L suppresses amyloidogenic cleavage of mAPP by direct binding of X11L through its PTB domain, thereby generation of A beta lowers. X11L expresses another function in the regulation of intracellular APP trafficking. Methodology: In order to analyze novel function of X11L in intracellular trafficking of APP, we performed a functional dissection of X11L. Using cells expressing various domain-deleted X11L mutants, intracellular APP trafficking was examined along with analysis of APP metabolism including maturation (O-glycosylation), processing and localization of APP. Conclusions: X11L accumulates imAPP into the early secretory pathway by mediation of its C-terminal PDZ domains, without being bound to imAPP directly. With this novel function, X11L suppresses overall APP metabolism and results in further suppression of Ab generation. Interestingly some of the accumulated imAPP in the early secretory pathway are likely to appear on plasma membrane by unidentified mechanism. Trafficking of imAPP to plasma membrane is observed in other X11 family proteins, X11 and X11L2, but not in other APP-binding partners such as FE65 and JIP1. It is herein clear that respective functional domains of X11L regulate APP metabolism at multiple steps in intracellular protein secretory pathways.

• 2011-07-19

著者

• Araki Yoichi

  Graduate School Of Pharmaceutical Sciences Hokkaido University

• Yamamoto Tohru

  Graduate School Of Pharmaceutical Sciences Hokkaido University

• Suzuki Toshiharu

  北海道大学 薬学研究科

• Sumioka Akio

  Laboratory Of Neurobiophysics Graduate School Of Pharmaceutical Sciences The University Of Tokyo

• Nakaya Tadashi

  Graduate School Of Pharmaceutical Sciences Hokkaido University

• Suzuki Toshiharu

  Graduate School Of Pharmaceutical Sciences Hokkaido University

関連論文

• Trafficking of Alzheimer's Disease-Related Membrane Proteins and Its Participation in Disease Pathogenesis
• Interaction of N-Terminal Acetyltransferase with the Cytoplasmic Domain of β-Amyloid Precursor Protein and Its Effect on Aβ Secretion
• Coordinated increase of γ-secretase reaction products in the plasma of some female Japanese sporadic Alzheimer's disease patients : quantitative analysis of p3-Alcα with a new ELISA system
• Constitutive Cleavage of the Single-Pass Transmembrane Protein Alcadeinα Prevents Aberrant Peripheral Retention of Kinesin-1
• Multiple γ-secretase product peptides are coordinately increased in concentration in the cerebrospinal fluid of a subpopulation of sporadic Alzheimer's disease subjects
• Coordinated increase of γ-secretase reaction products in the plasma of some female Japanese sporadic Alzheimer's disease patients: quantitative analysis of p3-Alcα with a new ELISA system.
• Multiple γ-secretase product peptides are coordinately increased in concentration in the cerebrospinal fluid of a subpopulation of sporadic Alzheimer's disease subjects.
• Increased amyloidogenic processing of transgenic human APP in X11-like deficient mouse brain
• Physiological mouse brain Abeta levels are not related to the phosphorylation state of threonine-668 of Alzheimer's APP.
• Intracellular Trafficking of the Amyloid beta-Protein Precursor (APP) Regulated by Novel Function of X11-Like

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