Yung-Feng Liao
Institute of Cellular and Organismic Biology, Taiwan
Keynote: J Neurol Neurophysiol
γ-Secretase-catalyzed production of amyloid-β (Aβ ) underlies the pathogenesis of Alzheimer??s Disease (AD). To identify genetic modifiers that can selectively affect -secretase cleavage of APP while sparing Notch cleavage, we generated cell-based assays employing Bioluminescence Resonance Energy Transfer (BRET) technology to monitor the protein-protein interactions between PS1 and two -secretase substrates, APP C-terminal fragment (C99) and extracellular domain truncated Notch (N?E). An RNAi screen identified 14 candidate genes whose down-regulation resulted in a selective decrease in the interaction between PS1 and C99. Among those 14 candidate genes, an ErbB2-centered interaction network was found to preferentially govern the proteostasis of APP-C99. We further demonstrated that overexpression of ErbB2 up-regulates the levels of C99 and AICD effectively. The knockdown of ErbB2 selectively decreased the protein levels of C99, AICD and secreted Aβ 40, but not those of N?E and NICD. Selective suppression of ErbB2 expression by CL-387,785, an ErbB1/2-selective irreversible tyrosine kinase inhibitor, can preferentially attenuate the levels of C99 and AICD, resulting in a significant reduction in Aβ production. Downregulation of ErbB2 by CL-387,785 also resulted in a significant decrease in the levels of C99 and secreted Aβ in both zebrafish and mouse models of AD, through the activation of autophagy. Oral administration of CL-387,785 for 3 week significantly improves the cognitive functions of APP/presenilin-1 (PS1) transgenic mice. These findings unveil a non-canonical function of ErbB2 in modulating autophagy and established ErbB2 as a novel therapeutic target for AD.
Yung-Feng Liao has completed his PhD in Biochemistry and Molecular Biology from University of Georgia, Athens, Georgia, USA and Postdoctoral studies from Harvard Medical School/Massachusetts General Hospital/Brigham and Women’s Hospital, Boston, Massachusetts, USA. He is the Principal Investigator of the Laboratory of Molecular Neurobiology in the Institute of Cellular and Organismic Biology, Academia Sinica, a premier research institution in Taiwan. He has published more than 50 papers in reputed journals and has been serving either as an Editorial Board Member or as a Peer Reviewer of prestigious journals.
E-mail: yliao@sinica.edu.tw
