Yung-Feng Liao

Title : Novel Pharmacological Targets of Alzheimer’s Disease

Abstract:

Alzheimer's disease (AD) is characterized by a chronic decline in cognitive function and is pathologically typified by cerebral deposition of amyloid-β peptide (Aβ). The production of Aβ is mediated by sequential proteolysis of amyloid precursor protein (APP) by β- and γ-secretase, which has been regarded as the amyloidogenic pathway of AD pathogenesis. An RNA interference-based screen has led us to identify an ErbB2-centered signaling network that preferentially govern the proteostasis of APP-C99, a direct substrate of γ-secretase. Down-regulation of ErbB2 by CL-387,785 decreases the levels of C99 and secreted Aβ in cellular, zebrafish, and mouse models of AD, through the activation of autophagy. Oral administration of CL-387,785 for 3 wk significantly improves the cognitive functions of APP/PS1 transgenic mice, establishing ErbB2 as a novel therapeutic target for AD. A previous report documents the significant correlation between lipid metabolism and incipient AD by using microarray correlation analyses. We thus attempt to determine the mechanism through which alterations in lipid compositions of biomembranes might contribute to the pathogenesis of AD. Given that the level of phosphatidylinositol-4,5-bisphosphate [PI(4,5)P2] in the membrane has been implicated to modulate Aβ production, we then investigate whether PIP5K type Iα (PIP5K1A) can affect Aβ production by modulating the PIP2 content of the membrane. Our data show that overexpression of PIP5K1A results in significant enhancement of nonamyloidogenic APP processing, leading to a marked decrease in secreted Aβ and a concomitant redistribution of APP from endosomal compartments to the cell surface. These results suggest that PIP5K1A may be a valuable therapeutic target for AD through its effect on promoting non-amyloidogenic processing of APP.

What will audience learn from your presentation?

• ErbB2 and PIP5K1A are identified as novel pharmacological targets of AD.
•  ErbB2-specific inhibitors could be derived from the molecular structure of CL-387,785.
• There is no PIP5K1A inhibitor available. How to generate chemical inhibitors that can modulate PIP2 content of cellular membranes could potentially contribute to a breakthrough in terms of expanding the therapeutic approaches for AD.

Biography:

Dr. Yung-Feng Liao studied Biochemistry at the National Yang-Ming Medical College, Taipei, Taiwan, and graduated as MS in 1987. After working as a research assistant at the Graduate Institute of Biological Chemistry, National Taiwan University, Taipei, Taiwan, Dr. Liao then joined the research group of Prof. Kelley Moremen at the Department of Biochemistry and Molecular Biology, University of Georgia, Athens, GA, USA, and obtained his PhD degree in 1998. After completing postdoctoral fellowship supervised by Dr. Livingston Van De Water at the Massachusetts General Hospital and Dr. Michael Wolfe at the Brighm and Women’s Hospital, Harvard Medical School, Boston, MA, USA, he obtained the faculty position at the Institute of Cellular and Organismic Biology, Academia Sinica, Taipei, Taiwan in 2002. Since then, Dr. Liao has been the principal investigator of the Laboratory of Molecular Neurobiology in the Institute of Cellular and Organismic Biology (ICOB), Academia Sinica, a premier research institution in Taiwan. Currently, Dr. Liao holds the rank of Research Fellow at the ICOB. He has published more than 60 papers in reputed journals and has been serving either as an editorial board member or as a peer reviewer of prestigious journals.