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bioRxiv · 10.1101/2025.03.26.645519

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

Dupuis, L.·Garcia, L.·Petit, F.·Lam, S.·Hirbec, H. E.·Picq, J.-L.·Boche, D.·Dhenain, M.
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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 are the resident macrophages of the central nervous system. They play crucial roles in maintaining brain homeostasis, yet their age-related changes remain not fully understood. While age-related microglia changes have been strongly characterized in rodents, studies in non-human primates are scarce. The microcebe primate (mouse lemur (Microcebus murinus)) is widely used as a model for cerebral aging and to investigate age-related neurodegenerative processes. HLA-DR is a major histocompatibility class II cell surface receptor which presents antigens to cells of the immune response. It is a major marker of microglia reaction. In this study, we explored microglia in the whole brains of middle-aged and old microcebes using HLA-DR immunolabeling. We analyzed microglial morphology and quantified HLA-DR+ cell density and protein expression. A wide range of microglial morphologies was observed in the white matter, including thin processes microglia, "rod-like" elongated and polarized shape, hypertrophic, and amoeboid microglia. Aging was associated with increased HLA-DR+ microglial expression in the white matter while very few HLA-DR+ microglia were observed in the parenchyma of cortical gray matter regions. A second finding was the higher number of HLA-DR+ perivascular macrophages in old animals. This study in a primate outlines that, in the absence of neurodegenerative processes, the most prominent signs of age-related microglia/macrophage changes are region-specific and concern white matter and perivascular regions. This emphasizes the need to target these regions to prevent cerebral aging. Main PointsO_LIHLA-DR+ microglia in Microcebus murinus primate show diverse morphologies and increase with age in white matter. C_LIO_LIHLA-DR+ perivascular macrophage load increase in aged animals. C_LI Table of Contents Image (TOCI) O_FIG O_LINKSMALLFIG WIDTH=167 HEIGHT=200 SRC="FIGDIR/small/645519v2_ufig1.gif" ALT="Figure 1"> View larger version (56K): org.highwire.dtl.DTLVardef@edb574org.highwire.dtl.DTLVardef@23f606org.highwire.dtl.DTLVardef@ed2e0borg.highwire.dtl.DTLVardef@169f059_HPS_FORMAT_FIGEXP M_FIG C_FIG

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Dupuis, L., Garcia, L., Petit, F., Lam, S., Hirbec, H. E., Picq, J.-L., Boche, D., Dhenain, M.. 2025-03-30. Increased white matter microglial reaction and perivascular macrophages in the aging microcebe primate. https://doi.org/10.1101/2025.03.26.645519

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