Details

Autor(en) / Beteiligte

• 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

Titel

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

Ist Teil von

• Proceedings of the National Academy of Sciences - PNAS, 2017-04, Vol.114 (15), p.E3129-E3138

Ort / Verlag

United States: National Academy of Sciences

Erscheinungsjahr

2017

Link zum Volltext

Quelle

EZB Electronic Journals Library

Beschreibungen/Notizen

• 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.