Understanding the Dynamic Lipid-Immunometabolome of Protective and Risk Alzheimer’s Microglia

Microglia are the major immune cells of our brain and play a key role in Alzheimer’s disease. Microglia clear brain waste that otherwise can become toxic, and also support other cell types, such as neurons. In Alzheimer’s disease, microglia become dysregulated and overactivated, leading to a toxic cycle of neuroinflammation. Interestingly, it was recently discovered that an overload of lipids (fats) strongly impairs the normal function of microglia in the brain of Alzheimer’s disease patients. Here we want to understand how lipids exactly regulate microglia. Specifically, we will study how genetic risk variants that increase or decrease the risk for Alzheimer’s disease affect how microglia respond to lipids. We predict that microglia that carry protective mutations are better equipped to handle lipid challenges and can revert faster to protective immune states. Instead, we think lipid challenges might lock Alzheimer’s-risk microglia into detrimental proinflammatory states. Overall, our work will provide more insights into the mechanism that causes neuroinflammation during the earliest steps of Alzheimer’s disease. Our research will help define novel targets for therapeutic interventions that can steer Alzheimer’s microglia to protective microglial states in order to prevent or even revert disease progression.