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 journalArticle

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

Keywords

  • Alzheimer’s disease
  • Autophagy
  • C99
  • ErbB2

ASJC Scopus subject areas

  • General

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    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. (2017). ErbB2 regulates autophagic flux to modulate the proteostasis of APP-CTFs in Alzheimer’s disease. Proceedings of the National Academy of Sciences of the United States of America, 114(15), E3129-E3138. https://doi.org/10.1073/pnas.1618804114