The microglial regulator CD33 controls brain amyloid-beta clearance in Alzheimer’s disease. We previously performed an unbiased high-throughput screen of FDA-approved medications and CD33-specific antibodies in microglia to identify effective CD33 inhibitors. We found medications that modulated amyloid-beta clearance and microglial activation state. We also found CD33-specific antibodies that dramatically reduced CD33 protein levels. Here, we propose to investigate the mechanisms through which the FDA-approved medications modulate amyloid-beta clearance and the levels of inflammatory mediators in microglia. We also will determine the effects of CD33-specific antibodies on amyloid beta clearance, microglial activation state and CD33-mediated signaling. The development of effective CD33 inhibitors might provide a novel therapeutic approach for this devastating disease.