PUBLICATION

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

Authors
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.
ID
ZDB-PUB-170330-4
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, A?, C99, ErbB2, autophagy
MeSH Terms
  • Animals
  • Zebrafish/genetics
  • Zebrafish/growth & development
  • Zebrafish/metabolism
  • Amyloid Precursor Protein Secretases/genetics
  • Amyloid Precursor Protein Secretases/metabolism*
  • Humans
  • Autophagy*
  • Brain/metabolism
  • Brain/pathology*
  • Beclin-1/genetics
  • Beclin-1/metabolism
  • Mice, Transgenic
  • Female
  • Alzheimer Disease/genetics
  • Alzheimer Disease/metabolism
  • Alzheimer Disease/pathology*
  • Male
  • Amyloid beta-Peptides/genetics
  • Amyloid beta-Peptides/metabolism
  • Proteostasis
  • Receptor, ErbB-2/genetics
  • Receptor, ErbB-2/metabolism*
  • Presenilin-1/genetics
  • Presenilin-1/metabolism*
  • Amyloid beta-Protein Precursor/genetics
  • Amyloid beta-Protein Precursor/metabolism*
  • Mice
(all 28)
PubMed
28351972 Full text @ Proc. Natl. Acad. Sci. USA
Abstract
Proteolytic processing of amyloid precursor protein (APP) C-terminal fragments (CTFs) by ?-secretase underlies the pathogenesis of Alzheimer's disease (AD). An RNA interference screen using APP-CTF [99-residue CTF (C99)]- and Notch-specific ?-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-? 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.
Genes / Markers
Figures
Figure Gallery (1 images)
Show all Figures
Expression
Phenotype
No data available
Mutations / Transgenics
No data available
Human Disease / Model
Human Disease Fish Conditions Evidence
Alzheimer's diseaseTAS
1 - 1 of 1
Show
Sequence Targeting Reagents
No data available
Fish
No data available
Antibodies
No data available
Orthology
No data available
Engineered Foreign Genes
No data available
Mapping
No data available
Your Input Welcome
We welcome your input and comments. Please use this form to recommend updates to the information in ZFIN. We appreciate as much detail as possible and references as appropriate. We will review your comments promptly.
Citation
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. (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.