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

Growing evidence has implicated a critical role for microglia in mediating Alzheimer’s disease (AD) pathogenesis, making them a promising target for AD therapeutics. Impaired microglial phagocytosis results in accumulation of amyloid beta (Aβ), leading to neuroinflammation, which is the primary driver of neurodegeneration. Through an unbiased high-throughput screen of a natural product (NP) library, we identified sesquiterpene lactone NPs that reduced levels of pro-inflammatory cytokines with high potency in microglia. We also performed an unbiased high-throughput screen of an FDA-approved drug library and identified calcium channel blockers that efficiently increased Aβ uptake in microglia. In this study, the sesquiterpene lactone NPs and calcium channel blocker compounds will be validated in dose-response cytokine release and Aβ uptake assays, respectively, in human microglial-like cells. Furthermore, we will investigate the mechanisms underlying the protective effects of these compounds in human microglial-like cells by using transcriptome profiling. These studies may facilitate the development of novel therapeutic approaches for AD based on targeting neuroinflammation and microglial function.