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

9 Citations (Scopus)

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

Fingerprint

Protein C
Amyloid
Alzheimer Disease
Amyloid Precursor Protein Secretases
Amyloid beta-Protein Precursor
Autophagy
Presenilin-1
Zebrafish
RNA Interference
Cognition
Transgenic Mice
Oral Administration
Hippocampus
Phosphotransferases
Down-Regulation
Brain
CL 387785
Therapeutics

Keywords

  • Alzheimer’s disease
  • Autophagy
  • C99
  • ErbB2

ASJC Scopus subject areas

  • General

Cite this

ErbB2 regulates autophagic flux to modulate the proteostasis of APP-CTFs in Alzheimer’s disease. / Wang, Bo Jeng; Her, Guor Mour; Hu, Ming Kuan; Chen, Yun Wen; Tung, Ying Tsen; Wu, Pei Yi; Hsu, Wen Ming; Lee, Hsinyu; Jin, Lee-Way; Hwang, Sheng Ping L.; Chen, Rita P.Y.; Huang, Chang Jen; Liao, Yung Feng.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 114, No. 15, 11.04.2017, p. E3129-E3138.

Research output: Contribution to journalArticle

Wang, BJ, Her, GM, Hu, MK, Chen, YW, Tung, YT, Wu, PY, Hsu, WM, Lee, H, Jin, L-W, Hwang, SPL, Chen, RPY, Huang, CJ & Liao, YF 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, vol. 114, no. 15, pp. E3129-E3138. https://doi.org/10.1073/pnas.1618804114
Wang, Bo Jeng ; Her, Guor Mour ; Hu, Ming Kuan ; Chen, Yun Wen ; Tung, Ying Tsen ; Wu, Pei Yi ; Hsu, Wen Ming ; Lee, Hsinyu ; Jin, Lee-Way ; Hwang, Sheng Ping L. ; Chen, Rita P.Y. ; Huang, Chang Jen ; Liao, Yung Feng. / ErbB2 regulates autophagic flux to modulate the proteostasis of APP-CTFs in Alzheimer’s disease. In: Proceedings of the National Academy of Sciences of the United States of America. 2017 ; Vol. 114, No. 15. pp. E3129-E3138.
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