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

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. We thank the Agence Nationale de la Recherche (PrimAlz, ANR-22-CE14-0056), Association France Alzheimer, Fondation Vaincre Alzheimer, Paris-Saclay University (Graduate School Life Sciences and Health) for funding this study. The MIRCen facility was funded by a grant from NeurATRIS: A Translational Research Infrastructure for Biotherapies in Neurosciences (“Investissements d’Avenir”, ANR-11-INBS-0011).

LG was financed by the French Ministère de l’Enseignement Supérieure, de la Recherche et de l’Innovation. All authors: Agence Nationale de la Recherche (PrimAlz, ANR-22-CE14-0056; “Investissements d’Avenir”, ANR-11-INBS-0011), Association France Alzheimer; LD:, Fondation Vaincre Alzheimer; LG: Paris-Saclay University (Graduate School Life Sciences and Health) ; French Ministère de l’Enseignement Supérieure, de la Recherche et de l’Innovation. Léo Dupuis and Lolie Garcia contributed equally: Léo Dupuis and Lolie Garcia.

Neuro-Bicêtre, Inserm U1195, CNRS EMR2000, Université Paris-Saclay, Bâtiment Gregory Pincus, 80 rue du Général Leclerc, Le Kremlin Bicêtre, 94276, France Léo Dupuis, Lolie Garcia, Jean-Luc Picq & Marc Dhenain Laboratoire des Maladies Neurodégénératives, Université Paris-Saclay, CEA, CNRS, 18 Route du Panorama, Fontenay-aux-Roses, F-92265, France Léo Dupuis, Lolie Garcia, Fanny Petit, Suzanne Lam, Jean-Luc Picq & Marc Dhenain Commissariat à l’Energie Atomique et aux Énergies Alternatives (CEA), Direction de la Recherche Fondamentale (DRF), MIRCen, Institut François Jacob, 18 Route du Panorama, Fontenay-aux-Roses, F-92265, France IGF, Université de Montpellier, CNRS, INSERM, Montpellier, France Clinical Neurosciences, Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton, UK The authors declare no competing interests. Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. Below is the link to the electronic supplementary material.