ZFIN ID: ZDB-PUB-170330-4
ErbB2 regulates autophagic flux to modulate the proteostasis of APP-CTFs in Alzheimer's disease
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.L., Chen, R.P., Huang, C.J., Liao, Y.F.
Date: 2017
Source: Proceedings of the National Academy of Sciences of the United States of America   114(15): E3129-E3138 (Journal)
Registered Authors: Her, Guor Muor, Huang, Chang-Jen, Hwang, Sheng-Ping L.
Keywords: Alzheimer’s disease, Aβ, C99, ErbB2, autophagy
MeSH Terms:
  • Alzheimer Disease/genetics
  • Alzheimer Disease/metabolism
  • Alzheimer Disease/pathology*
  • Amyloid Precursor Protein Secretases/genetics
  • Amyloid Precursor Protein Secretases/metabolism*
  • Amyloid beta-Peptides/genetics
  • Amyloid beta-Peptides/metabolism
  • Amyloid beta-Protein Precursor/genetics
  • Amyloid beta-Protein Precursor/metabolism*
  • Animals
  • Autophagy*
  • Beclin-1/genetics
  • Beclin-1/metabolism
  • Brain/metabolism
  • Brain/pathology*
  • Female
  • Humans
  • Male
  • Mice
  • Mice, Transgenic
  • Presenilin-1/genetics
  • Presenilin-1/metabolism*
  • Proteostasis
  • Receptor, ErbB-2/genetics
  • Receptor, ErbB-2/metabolism*
  • Zebrafish/genetics
  • Zebrafish/growth & development
  • Zebrafish/metabolism
PubMed: 28351972 Full text @ Proc. Natl. Acad. Sci. USA
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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.
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