Investigating the mechanisms of anti-amyloid antibodies and the role of microglia in amyloid plaque clearance in Alzheimer’s Disease

Alzheimer’s disease (AD) is a neurodegenerative disease and the leading cause of dementia worldwide. Despite decades of research, no curative treatment is available. Recently, monoclonal anti-amyloid-β antibodies have emerged as a promising therapeutic approach, offering hope for patients. Notably, Lecanemab is the first disease-modifying drug to be approved. Clinical trials show that Lecanemab reduces amyloid plaque load in the brain and slows cognitive decline in AD patients. However, concerns regarding the efficacy and safety of such antibodies remain, and their mechanisms of action are still unclear. Data from my host lab demonstrate that Lecanemab efficacy relies on activation of Fc fragment-dependent functions in human microglial cells. In the proposed project, I aim to conduct an in-depth characterization of the mechanisms by which Lecanemab enhances microglial plaque clearance. I will develop new tools to modulate Fc-dependent pathways and implement them both in vitro and in vivo to investigate the potential contributions of both FcγR activation and the complement system. I will leverage the innovative human microglia xenotransplantation model of AD developed in the lab. This will allow deciphering the key microglial downstream signaling pathways, which I will validate using an antisense oligonucleotide strategy. Overall, this project will provide critical insights for the development of safer and more effective treatments for Alzheimer's disease.