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

2018 and 2019

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.


Funding to Date

$345,000

Focus

Drug Discovery, Genes to Therapies™, Translational Research

Researchers

Ana Griciuc, Ph.D.