ErbB2 regulates autophagic flux to modulate the proteostasis of APP-CTFs in Alzheimer’s disease

Bo Jeng Wang, Guor Mour Her, Ming Kuan Hu, Yun Wen Chen, Ying Tsen Tung, Pei Yi Wu, Wen Ming Hsu, Hsinyu Lee, Lee Way Jin, Sheng Ping L. Hwang, Rita P.Y. Chen, Chang Jen Huang, Yung Feng Liao

Research output: Contribution to journalArticlepeer-review

39 Scopus citations

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.

Original languageEnglish
Pages (from-to)E3129-E3138
JournalProceedings of the National Academy of Sciences of the United States of America
Volume114
Issue number15
DOIs
StatePublished - 11 Apr 2017

Keywords

  • Alzheimer’s disease
  • Autophagy
  • C99
  • ErbB2

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