Single‐Cell Dissection of Microglial Dysfunction in Diabetes‐Associated Neurodegenerative Vulnerability

ABSTRACT

The molecular mechanisms linking type 2 diabetes to increased neurodegenerative risk remain poorly defined. Given the critical involvement of microglial dysfunction in neurodegeneration, we constructed a temporal single‐cell atlas integrating transcriptomic and epigenomic profiles of microglia from diabetic (db/db) and control (db/m) mice across the lifespan. We delineated a nonlinear, diabetes‐specific pathological trajectory characterized by early inflammatory activation, a mid‐stage inflection in neurodegeneration‐associated signaling and metabolic stress, and late‐stage dysfunction. Chromatin accessibility profiling revealed early and persistent epigenomic priming of neurodegeneration‐associated pathways, accompanied by stage‐specific enhancer rewiring. Pseudotime analysis identified a disease‐associated microglial (DAM) state as a candidate transition node, characterized by biased polarization and accelerated maturation under diabetic conditions. Targeted validation using freshly isolated microglia and primary microglial cultures further supported the early expansion of the DAM population, a bias toward homeostatic‐to‐DAM activation, and Arhgap15 ‐dependent regulation of phagocytic activity. Together, these findings identify microglial states and candidate regulatory pathways that may link diabetes to neurodegenerative vulnerability.