ErbB2 regulates autophagic flux to modulate the proteostasis of APP-CTFs in Alzheimer's disease.
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.
Mesh Terms:
Alzheimer Disease, Amyloid Precursor Protein Secretases, Amyloid beta-Peptides, Amyloid beta-Protein Precursor, Animals, Autophagy, Beclin-1, Brain, Female, Humans, Male, Mice, Mice, Transgenic, Presenilin-1, Proteostasis, Receptor, ErbB-2, Zebrafish
Alzheimer Disease, Amyloid Precursor Protein Secretases, Amyloid beta-Peptides, Amyloid beta-Protein Precursor, Animals, Autophagy, Beclin-1, Brain, Female, Humans, Male, Mice, Mice, Transgenic, Presenilin-1, Proteostasis, Receptor, ErbB-2, Zebrafish
Proc. Natl. Acad. Sci. U.S.A.
Date: Dec. 11, 2016
PubMed ID: 28351972
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