@article{91f49958957e4ffdbcdaaa73711bbee2,
title = "Human and mouse single-nucleus transcriptomics reveal TREM2-dependent and TREM2-independent cellular responses in Alzheimer{\textquoteright}s disease",
abstract = "Glia have been implicated in Alzheimer{\textquoteright}s disease (AD) pathogenesis. Variants of the microglia receptor triggering receptor expressed on myeloid cells 2 (TREM2) increase AD risk, and activation of disease-associated microglia (DAM) is dependent on TREM2 in mouse models of AD. We surveyed gene-expression changes associated with AD pathology and TREM2 in 5XFAD mice and in human AD by single-nucleus RNA sequencing. We confirmed the presence of Trem2-dependent DAM and identified a previously undiscovered Serpina3n+C4b+ reactive oligodendrocyte population in mice. Interestingly, remarkably different glial phenotypes were evident in human AD. Microglia signature was reminiscent of IRF8-driven reactive microglia in peripheral-nerve injury. Oligodendrocyte signatures suggested impaired axonal myelination and metabolic adaptation to neuronal degeneration. Astrocyte profiles indicated weakened metabolic coordination with neurons. Notably, the reactive phenotype of microglia was less evident in TREM2-R47H and TREM2-R62H carriers than in non-carriers, demonstrating a TREM2 requirement in both mouse and human AD, despite the marked species-specific differences.",
author = "Yingyue Zhou and Song, {Wilbur M.} and Andhey, {Prabhakar S.} and Amanda Swain and Tyler Levy and Miller, {Kelly R.} and Poliani, {Pietro L.} and Manuela Cominelli and Shikha Grover and Susan Gilfillan and Marina Cella and Ulland, {Tyler K.} and Konstantin Zaitsev and Akinori Miyashita and Takeshi Ikeuchi and Makoto Sainouchi and Akiyoshi Kakita and Bennett, {David A.} and Schneider, {Julie A.} and Nichols, {Michael R.} and Beausoleil, {Sean A.} and Ulrich, {Jason D.} and Holtzman, {David M.} and Artyomov, {Maxim N.} and Marco Colonna",
note = "Funding Information: M. Colonna receives research support from Pfizer, Amgen, Alector and Ono. Funding Information: We would like to thank K. Murphy and T. Murphy for generously providing us Irf8-overexpression constructs and Irf8–/– mice. We thank S. Kumar for the help with IF on human PPFE samples, and B. Zinselmeyer and B. Saunders for their help with confocal images. We thank B. Schmidt for helpful discussions. We thank I. Kawaki and the Collaborative Research Project of the BRI, Niigata University. A. Kakita is supported by the Strategic Research Program for Brain Sciences from Japan Agency for Medical Research and Development, AMED. This work was supported by the NIH (RF1 AG051485, R21 AG059176, and RF1 AG059082 to M. Colonna, RF1 AG047644 and R01 NS090934 to D.M.H., R15 GM119070 to M.R.N.), the Cure Alzheimer{\textquoteright}s Fund (to M. Colonna and D.M.H.) and the JPB Foundation (to D.M.H). Publisher Copyright: {\textcopyright} 2020, The Author(s), under exclusive licence to Springer Nature America, Inc.",
year = "2020",
month = jan,
day = "1",
doi = "10.1038/s41591-019-0695-9",
language = "English",
volume = "26",
pages = "131--142",
journal = "Nature Medicine",
issn = "1078-8956",
number = "1",
}