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Dual ontogeny of disease-associated microglia and disease inflammatory macrophages in aging and neurodegeneration

2022; Cell Press; Volume: 55; Issue: 8 Linguagem: Inglês

10.1016/j.immuni.2022.07.004

1097-4180

Aymeric Silvin, Stefan Uderhardt, Cécile Piot, Sandro Dá Mesquita, Katharine Yang, Laufey Geirsdóttir, Kevin Mulder, Eyal David, Zhaoyuan Liu, Cécile Bridlance, Morgane Sonia Thion, Xiao Meng Zhang, Wan Ting Kong, Marc Deloger, Vasco F. Fontes, Assaf Weiner, Pui Lai Rachel Ee, Regine J. Dress, Jing Hang, Akhila Balachander, Svetoslav Chakarov, Benoît Malleret, Garett Dunsmore, Olivier Cexus, Jinmiao Chen, Sonia Garel, Charles‐Antoine Dutertre, Ido Amit, Jonathan Kipnis, Florent Ginhoux,

Neurogenesis and neuroplasticity mechanisms

Brain macrophage populations include parenchymal microglia, border-associated macrophages, and recruited monocyte-derived cells; together, they control brain development and homeostasis but are also implicated in aging pathogenesis and neurodegeneration. The phenotypes, localization, and functions of each population in different contexts have yet to be resolved. We generated a murine brain myeloid scRNA-seq integration to systematically delineate brain macrophage populations. We show that the previously identified disease-associated microglia (DAM) population detected in murine Alzheimer's disease models actually comprises two ontogenetically and functionally distinct cell lineages: embryonically derived triggering receptor expressed on myeloid cells 2 (TREM2)-dependent DAM expressing a neuroprotective signature and monocyte-derived TREM2-expressing disease inflammatory macrophages (DIMs) accumulating in the brain during aging. These two distinct populations appear to also be conserved in the human brain. Herein, we generate an ontogeny-resolved model of brain myeloid cell heterogeneity in development, homeostasis, and disease and identify cellular targets for the treatment of neurodegeneration.