Alzheimer’s Disease Drug Discovery and Development Consortium: Modulating CD33 Function and Neuroinflammation as a Therapeutic Approach for Alzheimer’s Disease

The innate immune receptor CD33 inhibits brain amyloid beta clearance and promotes neuroinflammation in Alzheimer’s disease. CD33 is a very interesting target for developing therapeutics for the prevention and treatment of Alzheimer’s disease. We identified two CD33-specific antibodies that downregulated CD33 protein levels in microglia. These antibodies will be evaluated for their ability to inhibit CD33 activity in microglial cells. Through an unbiased high-throughput screen of a natural product library, we identified natural products that reduced levels of pro-inflammatory mediators in microglia. Several combinations of natural products showed additive effects in reducing levels of pro-inflammatory mediators in microglia. Furthermore, we are currently screening an FDA-approved drug library for modulation of amyloid beta uptake in microglia. Hits from the primary screen will be validated in dose-dependent amyloid beta uptake assays in microglia. These studies are expected to facilitate Alzheimer’s disease therapeutics based on modulation of neuroinflammation.