Microglial SIRPα loss promotes and accelerates aging-associated glial activation in white matter

Abstract In the aging brain, white matter is a major site of glial activation; however, the molecular mechanisms and key signaling molecules that govern this process remain poorly understood. Signal regulatory protein α (SIRPα) is a phagocytic checkpoint receptor expressed in microglia and macrophages. Microglia-specific deletion of SIRPα in mice (cKO mice) leads to the selective emergence of CD11c-positive microglia in white matter regions; notably, these mice exhibit attenuated demyelination in a cuprizone model, suggesting that SIRPα-deficient microglia may exert protective effects in white matter. Here, we show that CD11c-positive microglia were preferentially observed in the fimbria and periventricular region, white matter areas where a small number of CD11c-positive microglia are also detected in wild-type mice. Bulk RNA sequencing of the fimbria and optic nerve revealed that adult cKO mice already exhibited an aging-associated transcriptional profile, with upregulation of genes associated with white matter-associated microglia and astrocyte activation, along with modest induction of disease-associated oligodendrocyte genes. Immunohistochemical analysis confirmed a significant increase in glial fibrillary acidic protein-positive astrocytes specifically in white matter regions where CD11c-positive microglia were observed. Confocal imaging further demonstrated that activated microglia and reactive astrocytes were frequently found in close apposition. In contrast, oligodendrocyte lineage cells showed no overt histological changes. Canonical senescence effectors were not coherently induced, and the activated microglia retained Lamin B1 without accumulation of 53BP1 foci, indicating aging-associated activation rather than cellular senescence. Genotype-dependent glial activation remained evident in aged cKO mice, in which CD11c-positive microglia also accumulated lipofuscin-like granules, a histological feature of aged microglia. Despite exhibiting more pronounced aging-associated glial activation than aged control mice, aged cKO mice showed no overt MBP-defined myelin loss, and their motor performance in the rotarod test was significantly better preserved than that of aged control mice. These findings suggest that microglial SIRPα acts as a checkpoint molecule that restrains aging-associated glial activation in white matter, and that the resulting activation of microglia and astrocytes is not accompanied by overt MBP-defined myelin loss or accelerated motor decline. Whether this state reflects an adaptive response or an early, still-compensated stage of chronic activation remains to be determined.