A growing body of evidence suggests that Alzheimer’s disease involves a breakdown in how cells within the brain manage and recycle lipids and other cellular waste, leading to toxic buildup, inflammation, and loss of neural function. Our laboratory has identified PLA2G15 as a key regulator of a lipid called BMP that supports healthy lysosomal activity, and we have shown in another neurodegenerative disease model that removing PLA2G15 raises BMP levels and improves cellular clearance and cholesterol handling. This project will test whether enhancing BMP can provide similar benefits in Alzheimer’s disease by determining whether PLA2G15 deletion improves lysosomal function, reduces amyloid accumulation, limits neuroinflammation, and enhances memory and behavior in a well-established mouse model. We will also study human stem cell-derived microglia to understand how PLA2G15 interacts with APOE genetic variants that strongly influence Alzheimer’s risk, and we will begin developing small-molecule tools that target this pathway. By linking fundamental lipid biology to major genetic and pathological drivers of the disease, this work aims to establish a foundation for new therapeutic strategies and supports the mission of Cure Alzheimer’s Fund to advance innovative research with clear translational potential.
