| First Author | Wang BJ | Year | 2017 |
| Journal | Proc Natl Acad Sci U S A | Volume | 114 |
| Issue | 15 | Pages | E3129-E3138 |
| PubMed ID | 28351972 | Mgi Jnum | J:242145 |
| Mgi Id | MGI:5904545 | Doi | 10.1073/pnas.1618804114 |
| Citation | Wang BJ, et al. (2017) ErbB2 regulates autophagic flux to modulate the proteostasis of APP-CTFs in Alzheimer's disease. Proc Natl Acad Sci U S A 114(15):E3129-E3138 |
| abstractText | 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. |
