John Varghese
University of California Los Angeles, USA
Scientific Tracks Abstracts: Neurochem Neuropharm
Alzheimerâ��s disease (AD) is characterized by the presence of amyloid-�² (A�²) plaques in brain tissue. A�² is generated by sequential cleavage of full-length amyloid precursor protein (APP) by �² and �³ secretase. In an alternative pathway, �± secretase cleavage of APP produces the protein fragment sAPP�±, known to have trophic effects which support synaptic maintenance and memory. Proteolytic cleavage of APP by the �² secretase BACE1 (BACE) as the initial step in production of A�² has been a major target of AD drug discovery efforts. Overproduction of A�² results in neuronal cell death and accumulation of amyloid plaques in AD and traumatic brain injury (TBI) and is also associated with stroke due to cerebral amyloid angiopathy (CAA). Others have observed in cells that A�² production is reduced in the presence of increased sAPP�±. We therefore performed studies to determine the mechanism and revealed for the first time that sAPP�± is a potent endogenous direct inhibitor of the BACE enzyme and that this inhibition is likely by an allosteric mechanism. Furthermore, using small-angle X-ray scattering (SAXS), we show that sAPP�², which is identical to sA�²PP�± except for a 16-amino acid truncation at the carboxy terminus, adopts a completely different conformational structure than sAPP�± and importantly, does not inhibit BACE. Our data thus reveal a novel mechanistic role played by sAPP�± in regulating overproduction of A�² and restoring neuronal homeostasis and neuroprotection. Identification of sAPP�± as a direct BACE inhibitor would lead to the design of new therapeutics targeting pathologies associated with overproduction of A�². In this regard, we have identified through screening a repurposed drug F03 used in the treatment of post-operative nausea and vomiting (PONV) that increases sAPP�± in the brain and is currently in a Phase1b/2a clinical trial in Australia in subjects with MCI due to AD.
John Varghese has received his PhD from the Department of Medicinal Chemistry, University of Minnesota in 1985. He has obtained a Postdoctoral fellowship in Professor Josef Fried’s lab in the Department of Chemistry, University of Chicago and a second Postdoctoral fellowship in Professor Carl Djerassi’s lab in the Department of Chemistry at Stanford University. He has worked with Athena Neurosciences/Elan Pharmaceuticals as a Senior Member of their Discovery team for 18 years. He has then joined the Buck Institute for Research on Aging where he was Director of Alzheimer’s Drug Discovery Network. He has started the Drug Discovery Lab at UCLA in 2015.
Email: vjohn@mednet.ucla.edu
