Spatial mapping and senolytic targeting of senescent and disease-associated microglia in aged mouse brain white matter.

Abstract

Brain white matter undergoes structural and functional alterations linked to late-life cognitive decline, but the cellular and molecular basis of its selective vulnerability remains incompletely defined. Here, in naturally aged mice, we demonstrate that senescent and disease-associated microglia (DAM) phenotypes converge in hippocampal-adjacent white matter, particularly in the fimbria. Using regional gene expression profiling, immunolabeling, GeoMx digital spatial profiling and CosMx spatial molecular imaging, we identify an aged brain-exclusive microglial population concentrated in white matter that expresses DAM genes together with a 'SenBrain' senescence gene signature, including galectin-3 (GAL3/Lgals3). Single-cell spatial trajectory analyses suggest that multiple cell fate transitions may give rise to this aged, proinflammatory, senescent- and DAM-linked state. Pharmacogenetic or pharmacological senotherapeutic interventions reduced white matter GAL3⁺ DAM abundance and restored a more youthful microglial organization in aged fimbria. These findings identify a senescence- and DAM-enriched microglial state as a prominent and partially reversible feature of aged brain white matter.