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.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.WangHer G.M.Hu M.-K.Chen Y.-W.Tung Y.-T.Wu P.-Y.WEN-MING HSULee H.Jin L.-W.Hwang S.-P.L.Chen R.P.-Y.Huang C.-J.HSINYU LEE2020-03-052020-03-0520170027-8424https://www.scopus.com/inward/record.uri?eid=2-s2.0-85035053134&doi=10.1073%2fpnas.1618804114&partnerID=40&md5=28e86a2524929b443a907348d8fcd281https://scholars.lib.ntu.edu.tw/handle/123456789/469972Proteolytic 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]SDG3amyloid 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; Zebrafishjournal article10.1073/pnas.1618804114283519722-s2.0-85035053134