Normal aging increases white matter microglial reaction and perivascular macrophages in the microcebe primate

Abstract As populations age, the incidence of neurodegenerative disorders is rising. Early age-related neuropathological changes are the breeding ground for the development of these disorders. Microglia, the resident macrophages of the central nervous system, are essential for brain homeostasis, but their age-related changes remain poorly understood—especially in non-human primates. This study used the microcebe primate ( Microcebus murinus ), a model for cerebral aging, to investigate microglia and macrophages in middle-aged and old individuals using pan-microglial (Iba1) and activation (HLA-DR) markers. Notably, white matter showed a pronounced Iba1 and HLA-DR microglial activation, indicating its heightened vulnerability during aging. We also identified heterogeneity in microglial labeling and a diverse range of microglial morphologies in white matter. Additionally, aged animals exhibited white matter atrophy associated with white matter CD3 + T cells infiltration and increased perivascular macrophage labeling in the gray matter, suggesting altered immune surveillance. This latter was correlated with HLA-DR microglial activation in white matter, suggesting a global process. This primate study reveals that, in the absence of neurodegenerative processes, the most significant age-related microglial changes occur in white matter and outlines the importance of perivascular macrophages. These findings underscore the importance of targeting these areas to mitigate cerebral aging.