Validation and Characterization of Compounds Modulating Neuroinflammation and Amyloid Beta Uptake in Microglial Cells

Genetic studies of Alzheimer’s disease (AD) have revealed many AD-associated genes involved with neuroinflammation and microglial function. Microglial cells have emerged as a pharmacological target for the treatment of AD. While microglia can clear amyloid beta, they can also release pro-inflammatory cytokines leading to neuroinflammation. Through an unbiased high-throughput screen of a natural product (NP) library, we identified sesquiterpene lactone NPs that reduced levels of pro- inflammatory cytokines released by microglia. We also screened an FDA-approved drug library and identified calcium channel blockers that increased amyloid beta uptake in microglia. Furthermore, we validated the sesquiterpene lactone NPs and calcium channel blockers in dose-response cytokine release and amyloid beta uptake assays, respectively, in human microglia-like cells. Our ongoing studies are focused on investigating the mechanisms underlying the effects of these compounds in human microglia-like cells by using transcriptome profiling. This study will allow us to gain an improved understanding of our translational efforts to boost protective microglial cell functions in AD.