title: ErbB2 regulates autophagic flux to modulate the proteostasis of APP-CTFs in Alzheimer's disease.
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.
authors.affiliation: Institute of Cellular and Organismic Biology, Academia Sinica, Taipei 11529, Taiwan.
authors.forename: Bo-Jeng
authors.initials: BJ
authors.lastname: Wang
authors.affiliation: Institute of Bioscience and Biotechnology, National Taiwan Ocean University, Keelung 20224, Taiwan.|Center of Excellence for Marine Bioenvironment and Biotechnology, National Taiwan Ocean University, Keelung 20224, Taiwan.
authors.forename: Guor Mour
authors.initials: GM
authors.lastname: Her
authors.affiliation: School of Pharmacy, National Defense Medical Center, Taipei 114, Taiwan.
authors.forename: Ming-Kuan
authors.initials: MK
authors.lastname: Hu
authors.affiliation: Institute of Cellular and Organismic Biology, Academia Sinica, Taipei 11529, Taiwan.
authors.forename: Yun-Wen
authors.initials: YW
authors.lastname: Chen
authors.affiliation: Institute of Cellular and Organismic Biology, Academia Sinica, Taipei 11529, Taiwan.
authors.forename: Ying-Tsen
authors.initials: YT
authors.lastname: Tung
authors.affiliation: Institute of Cellular and Organismic Biology, Academia Sinica, Taipei 11529, Taiwan.
authors.forename: Pei-Yi
authors.initials: PY
authors.lastname: Wu
authors.affiliation: Department of Surgery, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei 10002, Taiwan.
authors.forename: Wen-Ming
authors.initials: WM
authors.lastname: Hsu
authors.affiliation: Department of Life Science, National Taiwan University, Taipei 10617, Taiwan.
authors.forename: Hsinyu
authors.initials: H
authors.lastname: Lee
authors.affiliation: Department of Pathology and Laboratory Medicine, Alzheimer's Disease Center, University of California Davis Medical Center, Sacramento, CA 95817.
authors.forename: Lee-Way
authors.initials: LW
authors.lastname: Jin
authors.affiliation: Institute of Cellular and Organismic Biology, Academia Sinica, Taipei 11529, Taiwan.
authors.forename: Sheng-Ping L
authors.initials: SL
authors.lastname: Hwang
authors.affiliation: Institute of Biological Chemistry, Academia Sinica, Taipei 11529, Taiwan.
authors.forename: Rita P-Y
authors.initials: RP
authors.lastname: Chen
authors.affiliation: Institute of Biological Chemistry, Academia Sinica, Taipei 11529, Taiwan.
authors.forename: Chang-Jen
authors.initials: CJ
authors.lastname: Huang
authors.affiliation: Institute of Cellular and Organismic Biology, Academia Sinica, Taipei 11529, Taiwan; yliao@sinica.edu.tw.|Department of Life Science, National Taiwan University, Taipei 10617, Taiwan.
authors.forename: Yung-Feng
authors.initials: YF
authors.lastname: Liao
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D053829:Amyloid Precursor Protein Secretases / Q000235:genetics / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000235:genetics / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001343:Autophagy; D000071186:Beclin-1 / Q000235:genetics / Q000378:metabolism; D001921:Brain / Q000378:metabolism / Q000473:pathology*; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D053764:Presenilin-1 / Q000235:genetics / Q000378:metabolism*; D000074702:Proteostasis; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D015027:Zebrafish / Q000235:genetics / Q000254:growth & development / Q000378:metabolism
chemical_list: D053829:Amyloid Precursor Protein Secretases; D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D000071186:Beclin-1; D053764:Presenilin-1; D018719:Erb-b2 Receptor Tyrosine Kinases; C508053:ERBB2 protein, human
keywords: Alzheimer’s disease; Aβ; C99; ErbB2; autophagy