Unlocking TREM2 Biology to Enable New Therapeutic Strategies for Alzheimer’s Disease

Dr. Griciuc proposes to determine how genetic variants of TREM2, one of the strongest Alzheimer’s disease (AD) risk genes expressed in microglia, alter immune cell function and influence disease progression. Although TREM2 has become a major therapeutic target, emerging evidence suggests that simply increasing TREM2 activity may not always be beneficial. Building on the team’s discovery that a gain-of-function TREM2 mutation (T96K) unexpectedly increases AD risk by impairing microglial function, the project will define how TREM2 mutations affect inflammation, lipid and energy metabolism, and cellular aging. The project integrates human stem cell-derived microglia, genetically engineered mouse models, and multi-omics approaches to dissect TREM2 biology. The team will investigate how TREM2 mutations alter inflammatory signaling, amyloid clearance, immune activation, and cellular energy metabolism in human stem cell-derived microglia. The study will also examine whether different TREM2 mutations modulate microglial senescence, a dysfunctional aging state linked to neurodegeneration, in human stem cell-derived microglia and mouse models of AD. Together, these studies aim to define the molecular consequences of distinct TREM2 mutations, identify therapeutic targets downstream of TREM2, and provide guidance for the development of precision therapies targeting microglial dysfunction in AD.