Santosh D'MelloLink to Webpage
Louisiana State University Shreveport
Preclinical Development of Small Molecule Therapeutics for Alzheimer's Disease
Xiaohong Lu, Louisiana State University Health Shreveport
Translational (May 1, 2022 - April 30, 2023)
Alzheimer's disease (AD) is a fatal neurodegenerative disease characterized by progressive cognitive impairment starting with a decline in memory. Despite a multitude of clinical trials there is currently no treatment that can stop or slow down the relentless loss of neurons in AD (or any other neurodegenerative disease). Several years ago, my lab discovered that a commercially-available compound, GW5074, belonging to the 3'-indolone class and sold as an inhibitor of c-Raf, was highly neuroprotective in cell culture as well as animal models of neurodegenerative disease. Starting with GW5074 we identified several other 3'-substituted indolones that were also neuroprotective, but that appeared to work through mechanisms different from GW5074. The model we used to evaluated neuroprotection by these compounds was cultured cerebellar granule neurons (CGNs) which die when switched from depolarizing medium to non-depolarizing medium. While an excellent in vitro model to study activity-dependent regulation of neuronal survival during development, the CGN model has limited relevance to age-associated neurodegenerative diseases, like AD. As a step towards developing effective therapeutics for the treatment of Alzheimer's disease, we will test a panel of 8 compounds identified in the CGN model using mouse hippocampal HT22 cells, a neuronal cell line well-suited for mechanistic studies on AD.