Aging and neurodegeneration: when systemic dysregulations affect brain macrophage heterogeneity

Microglia, the major population of brain resident macrophages, differentiate from yolk sac progenitors in the embryo and play multiple nonimmune roles in brain organization throughout development and life. Various microglia subtypes have been described by transcriptomic and proteomic signatures, involved metabolic pathways, morphology, intracellular complexity, time of residency, and ontogeny, both in development and in disease settings. Such macrophage heterogeneity increases with aging or neurodegeneration. Monocytes' infiltration and differentiation into monocyte-derived macrophages (MDMs) in the brain contribute to this diversity. Microbiota's role in brain diseases has been recently highlighted, revealing how microbial signals, such as metabolites, influence microglia and MDMs. In this brief review, we describe how these signals can influence microglia through their sensome and shape MDMs from their development in the bone marrow to their differentiation in the brain. Monocytes could then be a crucial player in the constitution of a dysbiotic gut-brain axis in neurodegenerative diseases and aging.