http://scholars.ntou.edu.tw/handle/123456789/20379
標題: | ErbB2 regulates autophagic flux to modulate the proteostasis of APP-CTFs in Alzheimer's disease | 作者: | 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 |
關鍵字: | AMYLOID PRECURSOR PROTEIN;RESONANCE ENERGY-TRANSFER;GAMMA-SECRETASE;INTRACELLULAR DOMAIN;NEURITIC PLAQUES;TRANSGENIC MICE;BETA PEPTIDE;MOUSE MODEL;RECEPTOR;DEPOSITION | 公開日期: | 11-四月-2017 | 出版社: | NATL ACAD SCIENCES | 卷: | 114 | 期: | 15 | 起(迄)頁: | E3129-E3138 | 來源出版物: | P NATL ACAD SCI USA | 摘要: | Proteolytic processing of amyloid precursor protein (APP) C-terminal fragments (CTFs) by gamma-secretase underlies the pathogenesis of Alzheimer's disease (AD). An RNA interference screen using APP-CTF [99-residue CTF (C99)]- and Notch-specific gamma-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-beta 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. |
URI: | http://scholars.ntou.edu.tw/handle/123456789/20379 | ISSN: | 0027-8424 | DOI: | 10.1073/pnas.1618804114 |
顯示於: | 03 GOOD HEALTH AND WELL-BEING |
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