Inhibiting CD33 Function and Modulating Microglial Activation State for Alzheimer’s Disease Therapy

2019

The microglial regulator CD33 controls brain amyloid beta clearance in Alzheimer’s disease. Through an unbiased high-throughput screen, we identified medications that increased amyloid beta uptake and maintained microglia in an anti-inflammatory activation state. CD33-specific antibodies that dramatically reduced CD33 levels also were identified. This project will investigate the mechanism of action of four FDA-approved medications that were highly effective at increasing amyloid beta uptake and reducing inflammation in microglia. We also will screen a natural product library for modulation of amyloid beta uptake and inflammation in microglia. We will investigate the effects of two CD33-specific antibodies on CD33 activity, inflammation and CD33-mediated signaling. To identify CD33 inhibitors, we also will screen anti-sense RNA targeting CD33 in microglia. Effective anti-inflammatory medications and CD33 inhibitors have the potential to provide a novel therapeutic approach for this devastating disease.

2018

High-throughput screens are scientific methods that enable hundreds of thousands of experimental samples to be tested under identical conditions. They are used to identify the targets that modulate a specific biological pathway. Using this technology, medications were identified that increased amyloid beta uptake and maintained an anti-inflammatory state in the brain. One of the regulators of amyloid beta clearance in Alzheimer’s disease is a microglial regulator called CD33. The screen identified CD33-specific antibodies that dramatically reduced CD33 levels. This project will investigate the mechanism of action of four FDA-approved medications that were highly effective at increasing amyloid beta uptake and reducing inflammation in microglia. Effective anti-inflammatory medications and CD33 inhibitors have the potential to provide a novel therapeutic approach for Alzheimer’s disease.