@article{635c904f940e4b90af454f6c89fd050c,
title = "Dual ontogeny of disease-associated microglia and disease inflammatory macrophages in aging and neurodegeneration",
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.",
keywords = "Alzheimer's disease, aging, disease inflammatory macrophages, disease-associated microglia, macrophage, microglia, neurodegeneration",
author = "Aymeric Silvin and Stefan Uderhardt and Cecile Piot and {Da Mesquita}, Sandro and Katharine Yang and Laufey Geirsdottir and Kevin Mulder and David Eyal and Zhaoyuan Liu and Cecile Bridlance and Thion, {Morgane Sonia} and Zhang, {Xiao Meng} and Kong, {Wan Ting} and Marc Deloger and Vasco Fontes and Assaf Weiner and Rachel Ee and Regine Dress and Hang, {Jing Wen} and Akhila Balachander and Svetoslav Chakarov and Benoit Malleret and Garett Dunsmore and Olivier Cexus and Jinmiao Chen and Sonia Garel and Dutertre, {Charles Antoine} and Ido Amit and Jonathan Kipnis and Florent Ginhoux",
note = "Funding Information: We thank all the laboratory's members for helpful discussions. Flow cytometry, cell sorting, and RNA library preparation were carried out on SIgN platforms established by A∗STAR Singapore. SIgN platforms are supported by a BMRC IAF311006 grant and BMRC transition funds #H16/99/b0/011 from A∗STAR. S.U. is supported by DFG (448121430, 448121523, and 405969122) and by ERC starting grant (101039438). F.G. is supported by EMBO YIP, SIgN core funding (A∗STAR) and Singapore NRF Senior Investigatorship (NRFI2017-02). B.M. was funded by NUHS Start-up grant (NUHSRO/2018/006/SU/01) and core funds from SIgN/A∗STAR. We also thank the Electron Microscopy Unit, National University of Singapore and the Research Support Centre A∗STAR Microscopy Platform for Electron Microscopy and Analysis. We thank Insight Editing London for their help. Conceptualization, A.S. and F.G.; methodology, A.S. C.P. S.U. and F.G.; investigation, A.S. S.U. C.P. S.D.M. K.Y. K.M. M.S.T. O.C. and F.G.; formal analysis, A.S. C.P. X.M.Z. K.M. G.D. M.D. B.M. J.C. and F.G.; data curation, A.S. S.U. S.D.M. K.Y. L.G. D.E. Z.L. C.B. M.S.T. W.T.K. A.W. R.E. R.D. J.W.H. A.B. and S.C.; writing, A.S. and F.G.; visualization, A.S. J.C. S.G. C.A.D. I.A. J.K. and F.G.; resource, S.U. M.D. B.M. O.C. J.C. S.G. A.M.B. I.A. J.K. and F.G.; funding acquisition, F.G.; supervision, F.G. A.S. and F.G. are inventors on a patent filed, owned, and managed by A∗ccelerate technologies Pte Ltd, A∗STAR, Singapore, on technology related to the work presented in this manuscript. Funding Information: We thank all the laboratory{\textquoteright}s members for helpful discussions. Flow cytometry, cell sorting, and RNA library preparation were carried out on SIgN platforms established by A ∗ STAR Singapore. SIgN platforms are supported by a BMRC IAF311006 grant and BMRC transition funds # H16/99/b0/011 from A∗STAR . S.U. is supported by DFG ( 448121430 , 448121523 , and 405969122 ) and by ERC starting grant ( 101039438 ). F.G. is supported by EMBO YIP , SIgN core funding ( A ∗ STAR ) and Singapore NRF Senior Investigatorship ( NRFI2017-02 ). B.M. was funded by NUHS Start-up grant ( NUHSRO/2018/006/SU/01 ) and core funds from SIgN/A ∗ STAR. We also thank the Electron Microscopy Unit, National University of Singapore and the Research Support Centre A ∗ STAR Microscopy Platform for Electron Microscopy and Analysis. We thank Insight Editing London for their help. Publisher Copyright: {\textcopyright} 2022 Elsevier Inc.",
year = "2022",
month = aug,
day = "9",
doi = "10.1016/j.immuni.2022.07.004",
language = "English",
volume = "55",
pages = "1448--1465.e6",
journal = "Immunity",
issn = "1074-7613",
number = "8",
}