https://scholars.lib.ntu.edu.tw/handle/123456789/469972
Title: | ErbB2 regulates autophagic flux to modulate the proteostasis of APP-CTFs in Alzheimer’s disease | Authors: | Wang, B.-J., Her, G.M., Hu, M.-K., Chen, Y.-W., Tung, Y.-T., Wu, P.-Y., Hsu, W.-M., Lee, H., Jin, L.-W., Hwang, S.-P.L., Chen, R.P.-Y., Huang, C.-J., Liao, Y.-F. Her G.M. Hu M.-K. Chen Y.-W. Tung Y.-T. Wu P.-Y. WEN-MING HSU Lee H. Jin L.-W. Hwang S.-P.L. Chen R.P.-Y. Huang C.-J. HSINYU LEE |
Issue Date: | 2017 | Publisher: | National Academy of Sciences | Journal Volume: | 114 | Journal Issue: | 15 | Start page/Pages: | E3129-E3138 | Source: | Proceedings of the National Academy of Sciences of the United States of America | Abstract: | Proteolytic processing of amyloid precursor protein (APP) C-terminal fragments (CTFs) by γ-secretase underlies the pathogenesis of Alzheimer’s disease (AD). An RNA interference screen using APP-CTF [99-residue CTF (C99)]- and Notch-specific γ-secretase interaction assays identified a unique ErbB2-centered signaling network that was predicted to preferentially govern the proteostasis of APP-C99. Consistently, significantly elevated levels of ErbB2 were confirmed in the hippocampus of human AD brains. We then found that ErbB2 effectively suppressed autophagic flux by physically dissociating Beclin-1 from the Vps34–Vps15 complex independent of its kinase activity. Down-regulation of ErbB2 by CL-387,785 decreased the levels of C99 and secreted amyloid-β in cellular, zebrafish, and mouse models of AD, through the activation of autophagy. Oral administration of an ErbB2-targeted CL-387,785 for 3 wk significantly improves the cognitive functions of APP/presenilin-1 (PS1) transgenic mice. This work unveils a noncanonical function of ErbB2 in modulating autophagy and establishes ErbB2 as a therapeutic target for AD. ? 2017, National Academy of Sciences. All rights reserved. |
URI: | https://www.scopus.com/inward/record.uri?eid=2-s2.0-85035053134&doi=10.1073%2fpnas.1618804114&partnerID=40&md5=28e86a2524929b443a907348d8fcd281 https://scholars.lib.ntu.edu.tw/handle/123456789/469972 |
ISSN: | 0027-8424 | DOI: | 10.1073/pnas.1618804114 | SDG/Keyword: | amyloid beta protein; amyloid precursor protein; beclin 1; epidermal growth factor receptor 2; gamma secretase; mitogen activated protein kinase; Notch receptor; phosphatidylinositol 3 kinase; presenilin 1; protein serine threonine kinase VPS15; sequestosome 1; stress activated protein kinase; amyloid beta protein; amyloid precursor protein; beclin 1; epidermal growth factor receptor 2; ERBB2 protein, human; presenilin 1; secretase; Alzheimer disease; animal cell; animal experiment; animal model; Article; autophagy; carboxy terminal sequence; cognition; comparative study; controlled study; embryo; enzyme activity; female; hippocampus; human; human tissue; memory; mouse; neuropathology; newborn; nonhuman; Notch signaling; priority journal; protein expression; protein homeostasis; protein protein interaction; protein secretion; protein targeting; receptor down regulation; regulatory mechanism; spatial learning; zebra fish; Alzheimer disease; animal; brain; genetics; growth, development and aging; male; metabolism; pathology; protein homeostasis; transgenic mouse; Alzheimer Disease; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Amyloid Precursor Protein Secretases; Animals; Autophagy; Beclin-1; Brain; Female; Humans; Male; Mice; Mice, Transgenic; Presenilin-1; Proteostasis; Receptor, ErbB-2; Zebrafish |
Appears in Collections: | 醫學系 |
Items in DSpace are protected by copyright, with all rights reserved, unless otherwise indicated.