Novel Master Regulators of Microglial Phagocytosis and Repurposed FDA-approved Drug for Treatment of Alzheimer Disease

Summary Microglia, the innate immune cells of the brain, are essential determinants of late-onset Alzheimer’s Disease (LOAD) neuropathology. Here, we developed an integrative computational systems biology approach to construct causal network models of genetic regulatory programs for microglia in Alzheimer’s Disease (AD). This model enabled us to identify novel key driver (KDs) genes for microglial functions that can be targeted for AD pharmacotherapy. We prioritized FCER1G, HCK, LAPTM5, ITGB2, SLC1A2, PAPLN, GSAP, NTRK2 , and CIRBP as KDs of microglial phagocytosis promoting neuroprotection and/or neural repair. In vitro , shRNA knockdown of each KD significantly reduced microglial phagocytosis. We repurposed riluzole, an FDA-approved ALS drug that upregulates SLC1A2 activity, and discovered that it stimulated phagocytosis of Aβ1-42 in human primary microglia and decreased hippocampal amyloid plaque burden/phosphorylated tau levels in the brain of aged 3xTg-AD mice. Taken together, these data emphasize the utlility of our integrative approach for repurposing drugs for AD therapy.