ErbB2 regulates autophagic flux to modulate the proteostasis of APP-CTFs in Alzheimer’s disease
Journal
Proceedings of the National Academy of Sciences of the United States of America
Journal Volume
114
Journal Issue
15
Pages
E3129-E3138
Date Issued
2017
Author(s)
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.
Lee H.
Jin L.-W.
Hwang S.-P.L.
Chen R.P.-Y.
Huang C.-J.
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.
SDGs
Other Subjects
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
Publisher
National Academy of Sciences
Type
journal article