Alzheimer’s disease (AD) disrupts memory by overwhelming the brain’s ability to clear toxic proteins and by pushing immune cells, called microglia, into a chronically stressed state. A key—and often overlooked— feature of this devastating disorder is the buildup of lipid droplets: tiny fat stores that accumulate inside brain cells. When overloaded with fat, microglia— the immune cells of the brain— become less effective at “housekeeping” (such as clearing amyloid) and more prone to inflammatory signaling. The protein PLIN2 acts as a coat on these lipid droplets, stabilizing them and making the stored fats harder to recycle.
Our project tests a simple idea with far-reaching implications: if we dial down PLIN2 specifically in microglia, can we relieve their lipid burden, restore their cleaning capacity, and improve brain health in AD? In this study, we will genetically delete PLIN2 in microglia in an Alzheimer’s mouse model and measure effects on amyloid pathology, harmful cellular responses, and memory performance. In parallel, we will study human microglia made from stem cells— including cells carrying the gene called APOE4, a common genetic variant that strongly increases a person’s risk of developing AD risk. These experiments will help determine whether reducing PLIN2 similarly rescues microglial function in individuals at the highest risk for AD. To understand how PLIN2 control reshapes microglia, we will pair state-of-the-art single-cell and spatial gene mapping with detailed lipid and metabolism measurements.
Together, these experiments will reveal whether targeting PLIN2 can shift microglia from a disease-associated, lipid-laden state toward a resilient, protective one. If successful, this work establishes PLIN2 as a druggable lever for microglial repair and delivers human-relevant biomarkers to guide future therapeutic development.
