Biography
Biography: Varghese John
Abstract
Apolipoprotein ε4 (ApoE4) is a major genetic risk factor for sporadic, late-onset Alzheimer’s disease (AD). One protein target that is affected in the presence of ApoE4 is the major longevity determinant and NAD-dependent deacetylase sirtuin-1 (SirT1), which we showed to be decreased in the presence of ApoE4 (Theendakara, PNAS 2013). Recent reports also show that SirT1 levels are shown to be decreased in serum of AD patients (Kumar, PLoS One 2013). Through screening we have identified a brain-penetrant small molecule, A03, that increased the neuroprotective SirT1 protein levels in ApoE4-transfected cells, and we have recently tested its efficacy in vivo in a ApoE4 mouse model for AD. The preliminary results show that A03 treatment can increase in SirT1 levels in the mouse brain thus providing initial proof-of-concept for developing this drug candidate as a ApoE4-targeted therapeutic for AD. We are in the process of designing and synthesizing analogs of A03, and studying their effects on both the neuroprotective SirT1 and neurotoxic protein sirtuin-2 (SirT2) in ApoE4-transfected cells. In addition, we have also initiated high throughput screening (HTS) of the UCLA compound library to identify new ‘hits’ that increase SirT1 in the presence of ApoE4. Our data thus reveal a novel mechanism for developing targeted therapeutics for this major known risk factor for AD. A03 is a promising lead candidate that increases brain SirT1 levels and could be developed as an ApoE4-targeted therapeutic for AD. Synthesis, testing, and screening of new ‘hit-analogs’ could yield additional candidates for development as potential therapeutics for Mild Cognitive Impairment (MCI) and/or AD. The research is supported by funding from NIH (R01AG051386) and the UCLA Easton Center for AD Research.
