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Article: Prior activation state shapes the microglia response to antihuman TREM2 in a mouse model of Alzheimer's disease

TitlePrior activation state shapes the microglia response to antihuman TREM2 in a mouse model of Alzheimer's disease
Authors
KeywordsAlzheimer's disease
Amyloid beta
Microglia
Monoclonal antibody
TREM2
Issue Date2021
Citation
Proceedings of the National Academy of Sciences of the United States of America, 2021, v. 118, n. 3, article no. e2017742118 How to Cite?
AbstractTriggering 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.
Persistent Identifierhttp://hdl.handle.net/10722/334725
ISSN
2023 Impact Factor: 9.4
2023 SCImago Journal Rankings: 3.737
ISI Accession Number ID

 

DC FieldValueLanguage
dc.contributor.authorEllwanger, Daniel C.-
dc.contributor.authorWang, Shoutang-
dc.contributor.authorBrioschi, Simone-
dc.contributor.authorShao, Zhifei-
dc.contributor.authorGreen, Lydia-
dc.contributor.authorCase, Ryan-
dc.contributor.authorYoo, Daniel-
dc.contributor.authorWeishuhn, Dawn-
dc.contributor.authorRathanaswami, Palaniswami-
dc.contributor.authorBradley, Jodi-
dc.contributor.authorRao, Sara-
dc.contributor.authorCha, Diana-
dc.contributor.authorLuan, Peng-
dc.contributor.authorSambashivan, Shilpa-
dc.contributor.authorGilfillan, Susan-
dc.contributor.authorHasson, Samuel A.-
dc.contributor.authorFoltz, Ian N.-
dc.contributor.authorvan Lookeren Campagne, Menno-
dc.contributor.authorColonna, Marco-
dc.date.accessioned2023-10-20T06:50:12Z-
dc.date.available2023-10-20T06:50:12Z-
dc.date.issued2021-
dc.identifier.citationProceedings of the National Academy of Sciences of the United States of America, 2021, v. 118, n. 3, article no. e2017742118-
dc.identifier.issn0027-8424-
dc.identifier.urihttp://hdl.handle.net/10722/334725-
dc.description.abstractTriggering 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.-
dc.languageeng-
dc.relation.ispartofProceedings of the National Academy of Sciences of the United States of America-
dc.subjectAlzheimer's disease-
dc.subjectAmyloid beta-
dc.subjectMicroglia-
dc.subjectMonoclonal antibody-
dc.subjectTREM2-
dc.titlePrior activation state shapes the microglia response to antihuman TREM2 in a mouse model of Alzheimer's disease-
dc.typeArticle-
dc.description.naturelink_to_subscribed_fulltext-
dc.identifier.doi10.1073/PNAS.2017742118-
dc.identifier.pmid33446504-
dc.identifier.scopuseid_2-s2.0-85100119912-
dc.identifier.volume118-
dc.identifier.issue3-
dc.identifier.spagearticle no. e2017742118-
dc.identifier.epagearticle no. e2017742118-
dc.identifier.eissn1091-6490-
dc.identifier.isiWOS:000609633900046-

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