The immune system of the brain is distinct from that of the rest of the body, at least to a first approximation. Given improved tools and more research, scientists are finding that immune cells from the body do find their way into the brain. This seems to occur to a limited degree normally, in young people, but becomes more pronounced in later life. This is likely due to increasing dysfunction of the blood-brain barrier, specialized cells that line blood vessels that pass through the brain and collectively determine which cells and molecules are allowed to pass to and from the brain. When the barrier leaks, allowing unwanted cells and molecules to enter the brain, the result is usually harmful persistent inflammation in the nearby brain tissue.
Microglia are parenchymal brain macrophages that are established during embryogenesis and form a self-containing cellular compartment derived from the yolk sac that resists seeding with cells derived from adult hematopoiesis occurring in the bone marrow. We report that monocyte-derived macrophages (MoMΦs) accumulate in the brain of aging mice with distinct topologies, including the nigrostriatum and medulla but not the frontal cortex. Parenchymal MoMΦs adopt bona fide microglia morphology and expression profiles.
Unlike yolk-sac-derived microglia in the brain, due to their derivation from hematopoietic stem cells MoMΦs are exposed to somatic mutations that are associated with age-related clonal hematopoiesis. Indeed, using a chimeric transfer model, we show that the hematopoietic expression of DNMT3AR882H, a prominent human clonal hematopoiesis variant, renders MoMg pathogenic and promotes motor deficits resembling atypical Parkinsonian disorders. Collectively, we establish that MoMg progressively seed the brain of healthy aging mice, accumulate in selected areas, and, when carrying a somatic mutation associated with clonal hematopoiesis, can cause brain pathology.
Link: https://doi.org/10.1016/j.celrep.2025.115609
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