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

Aymeric Silvin, Stefan Uderhardt, Cecile Piot, Sandro Da Mesquita, Katharine Yang, Laufey Geirsdottir, Kevin Mulder, David Eyal, Zhaoyuan Liu, Cecile Bridlance, Morgane Sonia Thion, Xiao Meng Zhang, Wan Ting Kong, Marc Deloger, Vasco Fontes, Assaf Weiner, Rachel Ee, Regine Dress, Jing Wen Hang, Akhila BalachanderSvetoslav Chakarov, Benoit Malleret, Garett Dunsmore, Olivier Cexus, Jinmiao Chen, Sonia Garel, Charles Antoine Dutertre, Ido Amit, Jonathan Kipnis, Florent Ginhoux

Research output: Contribution to journalArticlepeer-review

10 Scopus citations

Abstract

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.

Original languageEnglish
Pages (from-to)1448-1465.e6
JournalImmunity
Volume55
Issue number8
DOIs
StatePublished - Aug 9 2022

Keywords

  • Alzheimer's disease
  • aging
  • disease inflammatory macrophages
  • disease-associated microglia
  • macrophage
  • microglia
  • neurodegeneration

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