气候变化领域集成服务门户(CCPortal): Prior activation state shapes the microglia response to antihuman TREM2 in a mouse model of Alzheimer's disease

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DOI	10.1073/PNAS.2017742118
	Prior activation state shapes the microglia response to antihuman TREM2 in a mouse model of Alzheimer's disease
	Ellwanger D.C.; Wang S.; Brioschi S.; Shao Z.; Green L.; Case R.; Yoo D.; Weishuhn D.; Rathanaswami P.; Bradley J.; Rao S.; Cha D.; Luan P.; Sambashivan S.; Gilfillan S.; Hasson S.A.; Foltz I.N.; van Lookeren Campagne M.; Colonna M.
发表日期	2021
ISSN	0027-8424
卷号	118 期号:3
英文摘要	Triggering receptor expressed on myeloid cells 2 (TREM2) sustains microglia response to brain injury stimuli including apoptotic cells, myelin damage, and amyloid β (Aβ). Alzheimer's disease (AD) risk is associated with the TREM2R47H variant, which impairs ligand binding and consequently microglia responses to Aβ pathology. Here, we show that TREM2 engagement by the mAb hT2AB as surrogate ligand activates microglia in 5XFAD transgenic mice that accumulate Aβ and express either the common TREM2 variant (TREM2CV) or TREM2R47H. scRNA-seq of microglia from TREM2CV-5XFAD mice treated once with control hIgG1 exposed four distinct trajectories of microglia activation leading to disease-associated (DAM), interferon-responsive (IFN-R), cycling (Cyc-M), and MHC-II expressing (MHC-II) microglia types. All of these were underrepresented in TREM2R47H-5XFAD mice, suggesting that TREM2 ligand engagement is required for microglia activation trajectories. Moreover, Cyc-M and IFN-R microglia were more abundant in female than male TREM2CV-5XFAD mice, likely due to greater Aβ load in female 5XFAD mice. A single systemic injection of hT2AB replenished Cyc-M, IFN-R, and MHC-II pools in TREM2R47H-5XFAD mice. In TREM2CV-5XFAD mice, however, hT2AB brought the representation of male Cyc-M and IFN-R microglia closer to that of females, in which these trajectories had already reached maximum capacity. Moreover, hT2AB induced shifts in gene expression patterns in all microglial pools without affecting representation. Repeated treatment with a murinized hT2AB version over 10 d increased chemokines brain content in TREM2R47H-5XFAD mice, consistent with microglia expansion. Thus, the impact of hT2AB on microglia is shaped by the extent of TREM2 endogenous ligand engagement and basal microglia activation. © 2021 National Academy of Sciences. All rights reserved.
英文关键词	Alzheimer's disease; Amyloid beta; Microglia; Monoclonal antibody; TREM2
语种	英语
scopus关键词	amyloid beta protein; gamma interferon inducible protein 10; interferon; interleukin 1beta; macrophage inflammatory protein 1beta; major histocompatibility antigen class 2; monoclonal antibody; monoclonal antibody hT2AB; triggering receptor expressed on myeloid cells 2; unclassified drug; amyloid beta protein; chemokine; immunoglobulin receptor; membrane protein; monoclonal antibody; neutralizing antibody; protein binding; TREM2 protein, human; Trem2 protein, mouse; Alzheimer disease; animal cell; animal experiment; animal model; Article; bioaccumulation; blood brain barrier; cell activation; cell fate; cell proliferation; concentration response; controlled study; female; gene expression; human; human cell; male; microglia; mouse; nonhuman; protein phosphorylation; qualitative analysis; RNA sequencing; single drug dose; Alzheimer disease; animal; brain; classification; disease model; drug effect; gene expression regulation; genetics; HEK293 cell line; kinetics; metabolism; microglia; mutation; pathology; sex factor; transgenic mouse; Alzheimer Disease; Amyloid beta-Peptides; Animals; Antibodies, Monoclonal; Antibodies, Neutralizing; Brain; Cell Proliferation; Chemokines; Disease Models, Animal; Female; Gene Expression Regulation; HEK293 Cells; Humans; Kinetics; Male; Membrane Glycoproteins; Mice; Mice, Transgenic; Microglia; Mutation; Protein Binding; Receptors, Immunologic; Sex Factors
来源期刊	Proceedings of the National Academy of Sciences of the United States of America
文献类型	期刊论文
条目标识符	http://gcip.llas.ac.cn/handle/2XKMVOVA/251202
作者单位	Genome Analysis Unit, Amgen Research, Amgen Inc., South San Francisco, CA 94080, United States; Department of Pathology and Immunology, Washington University School of Medicine, St Louis, MO 63110, United States; Department of Inflammation and Oncology, Amgen Research, Amgen Inc., South San Francisco, CA 94080, United States; Department of Biologics Discovery, Amgen Research, Amgen Inc., Burnaby, BC V5A1V7, Canada; Discovery Attribute Sciences, Amgen Research, Amgen Inc., South San Francisco, CA 94080, United States; Department of Biologics Optimization, Amgen Research, Amgen Inc., Thousand Oaks, CA 91320, United States; Department of Neuroscience, Amgen Research, Amgen Inc., Cambridge, MA 02142, United States; Department of Translational Safety and Bioanalytical Sciences, Amgen Research, Amgen Inc., Thousand Oaks, CA 91320, United States
推荐引用方式 GB/T 7714	Ellwanger D.C.,Wang S.,Brioschi S.,et al. Prior activation state shapes the microglia response to antihuman TREM2 in a mouse model of Alzheimer's disease[J],2021,118(3).
APA	Ellwanger D.C..,Wang S..,Brioschi S..,Shao Z..,Green L..,...&Colonna M..(2021).Prior activation state shapes the microglia response to antihuman TREM2 in a mouse model of Alzheimer's disease.Proceedings of the National Academy of Sciences of the United States of America,118(3).
MLA	Ellwanger D.C.,et al."Prior activation state shapes the microglia response to antihuman TREM2 in a mouse model of Alzheimer's disease".Proceedings of the National Academy of Sciences of the United States of America 118.3(2021).