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Dual ontogeny of disease-associated microglia and disease inflammatory macrophages in aging and neurodegeneration
Open accessAbstract
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.
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“Notably, the R47H missense mutation in triggering receptor expressed on myeloid cells 2 (TREM2) has been shown to significantly increase the risk of AD, with an odds ratio comparable to that of the APOE ε4 allele”
From PU.1 dictates β-amyloid-induced TREM2 expression upregulation in microglia in a transgenic model of Alzheimer’s disease (2025) · cites this paper as Silvin et al., 2022
In the citing paper
“However, the role of the peripheral immune system in AD-related neuroinflammation and neurodegeneration is still largely understudied (9, 10).”
From Understanding monocyte-driven neuroinflammation in Alzheimer’s disease using human cortical organoid microphysiological systems (2025) · cites this paper as [9]
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“Moreover, recent studies have reported that during aging or neurodegeneration, bone marrow-derived blood monocytes can infiltrate the brain through a disrupted blood-brain barrier (BBB) and differentiate into microglia-like cells, exhibiting transcriptional and functional similarity to brain-resident microglia13–15.”
From Somatic cancer variants enriched in Alzheimer’s disease microglia-like cells drive inflammatory and proliferative states (2026) · cites this paper as [15]
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“microglial-sEVs, play two distinct roles in various phases of CNS diseases [38–40].”
From M2 microglia-derived small extracellular vesicles modulate NSC fate after ischemic stroke via miR-25-3p/miR-93-5p-TGFBR/PTEN/FOXO3 axis (2025) · cites this paper as [39]
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Metadata
- Authors
- Silvin, A., Uderhardt, S., Piot, C., Da Mesquita, S., Yang, K., Geirsdottir, L., Mulder, K., Eyal, D., Liu, Z., Bridlance, C., Thion, M. S., Zhang, X. M., Kong, W. T., Deloger, M., Fontes, V., Weiner, A., Ee, R., Dress, R., Hang, J. W., Balachander, A., Chakarov, S., Malleret, B., Dunsmore, G., Cexus, O., Chen, J., Garel, S., Dutertre, C. A., Amit, I., Kipnis, J., & Ginhoux, F.
- Affiliations
- Agency for Science, Technology and Research (SG)
- Friedrich-Alexander-Universität Erlangen-Nürnberg (DE)
- Inserm (FR)
- Shanghai Jiao Tong University (CN)
- Centre National de la Recherche Scientifique (FR)
- Weizmann Institute of Science (IL)
- National University of Singapore (SG)
- Washington University in St. Louis (US)
- Corresponding author
- Ginhoux, Florent
- ORCID
- Silvin, Aymeric
- Uderhardt, Stefan
- Yang, Katharine
- Mulder, Kevin
- Liu, Zhaoyuan
- Thion, Morgane Sonia
- Zhang, Xiao Meng
- Kong, Wan Ting
- Deloger, Marc
- Fontes, Vasco
- Weiner, Assaf
- Dress, Regine
- Hang, Jing Wen
- Balachander, Akhila
- Chakarov, Svetoslav
- Dunsmore, Garett
- Cexus, Olivier
- Chen, Jinmiao
- Garel, Sonia
- Dutertre, Charles Antoine
- Amit, Ido
- Kipnis, Jonathan
- Ginhoux, Florent
- Venue
- Immunity
- Publisher
- Elsevier BV
- Published
- 2022-08
- Volume
- 55
- Issue
- 8
- Pages
- 1448-1465.e6
- ISSN
- 1074-7613 (ISSN-L)
- OpenAlex
- W4289794258
- Cited by
- 368
- References
- 69
- Citations by year
- 2026: 80 · 2025: 99 · 2024: 100 · 2023: 77 · 2022: 10
- FWCI
- 25.27
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.elsevier.com/tdm/userlicense/1.0/ (tdm)
- www.elsevier.com/legal/tdmrep-license (tdm)
- www.elsevier.com/open-access/userlicense/1.0/ (vor, 660 d)
- doi.org/10.15223/policy-017 (stm-asf)
- doi.org/10.15223/policy-037 (stm-asf)
- doi.org/10.15223/policy-012 (stm-asf)
- doi.org/10.15223/policy-029 (stm-asf)
- doi.org/10.15223/policy-004 (stm-asf)
- Locations
- Immunity (publishedVersion)
- PubMed (publishedVersion)
- HAL (submittedVersion)
- Topics
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Single-cell and spatial transcriptomics
- Health Sciences › Medicine › Clinical Neurology › Multiple Sclerosis Research Studies
- Keywords
- disease-associated microglia, brain macrophages, TREM2, monocyte-derived macrophages, border-associated macrophages, aging, neurodegeneration, Alzheimer's disease, neuroprotection, single-cell transcriptomics
- MeSH terms
- Aging, Alzheimer Disease, Animals, Brain, Humans, Macrophages, Membrane Glycoproteins, Receptors, Immunologic, Microglia, Mice
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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