The DOI matches its Crossref record; 44 of the 44 references it cites were found in a registry or an index.
Prior activation state shapes the microglia response to antihuman TREM2 in a mouse model of Alzheimer’s disease
Abstract
Significance: Alzheimer’s disease (AD) is the most common dementia; no therapy halts its progression. AD pathology, including amyloid-β (Aβ) plaques, neurofibrillary tangles, and synapse loss, triggers microglial responses that modulate disease course. The TREM2 receptor promotes microglia responses to pathology and a variant, TREM2 R47H , impairs ligand binding and increases AD risk. Employing scRNA-seq, we asked: can an anti-TREM2 antibody, acting as a surrogate ligand, stimulate microglia in mice that accumulate Aβ and express either the common TREM2 variant ( TREM2 CV ) or TREM2 R47H ? One systemic injection of anti-TREM2 restored microglia activation in TREM2 R47H mice but promoted limited activation in mice carrying TREM2 CV , which binds endogenous ligands. Thus, anti-TREM2 can strengthen microglial responses during AD, contingent on preexisting TREM2 engagement and basal activation.
Overview
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Verification
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
The cited source says what the claim attributes to it.
In the citing paper
“Microglia gradually alter their state in the presence of Aβ pathology, a process described as transitional states (t1–t6) from homeostatic to cycling (Cyc-M), IFN-responsive (IFN-R), MHC-II expressing (MHCII) and DAM-like61.”
From Immune checkpoint TIM-3 regulates microglia and Alzheimer’s disease (2025) · cites this paper as [61]
In the citing paper
“A significant difference was found only in human MG8 signature annotated as inflammatory61.”
From Immune checkpoint TIM-3 regulates microglia and Alzheimer’s disease (2025) · cites this paper as [61]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Citations
Cites
The amyloid hypothesis of Alzheimer's disease at 25 years
Selkoe, D. J., & Hardy, J. (2016) · EMBO Molecular Medicine · doi:10.15252/emmm.201606210 · Cited by 6,164
A Unique Microglia Type Associated with Restricting Development of Alzheimer’s Disease
Keren-Shaul, H., Spinrad, A., Weiner, A., Matcovitch-Natan, O., Dvir-Szternfeld, R., Ulland, T. K., David, E., Baruch, K., Lara-Astaiso, D., Toth, B., et al. (2017) · Cell · doi:10.1016/j.cell.2017.05.018 · Cited by 5,493
Self-citationTerry, R. D., Masliah, E., Salmon, D. P., Butters, N., DeTeresa, R., Hill, R., Hansen, L. A., & Katzman, R. (1991) · Annals of Neurology · doi:10.1002/ana.410300410 · Cited by 4,397
Oakley, H., Cole, S. L., Logan, S., Maus, E., Shao, P., Craft, J., Guillozet-Bongaarts, A., Ohno, M., Disterhoft, J., Van Eldik, L., et al. (2006) · The Journal of Neuroscience · doi:10.1523/jneurosci.1202-06.2006 · Cited by 3,530
Alzheimer Disease: An Update on Pathobiology and Treatment Strategies
Long, J. M., & Holtzman, D. M. (2019) · Cell · doi:10.1016/j.cell.2019.09.001 · Cited by 3,204
TREM2 Variants in Alzheimer's Disease
Guerreiro, R., Wojtas, A., Bras, J., Carrasquillo, M., Rogaeva, E., Majounie, E., Cruchaga, C., Sassi, C., Kauwe, J. S. K., Younkin, S., et al. (2013) · New England Journal of Medicine · doi:10.1056/nejmoa1211851 · Cited by 3,020
Krasemann, S., Madore, C., Cialic, R., Baufeld, C., Calcagno, N., El Fatimy, R., Beckers, L., O’Loughlin, E., Xu, Y., Fanek, Z., et al. (2017) · Immunity · doi:10.1016/j.immuni.2017.08.008 · Cited by 2,979
Variant of TREM2 Associated with the Risk of Alzheimer's Disease
Jonsson, T., Stefansson, H., Steinberg, S., Jonsdottir, I., Jonsson, P. V., Snaedal, J., Bjornsson, S., Huttenlocher, J., Levey, A. I., Lah, J. J., et al. (2013) · New England Journal of Medicine · doi:10.1056/nejmoa1211103 · Cited by 2,558
Jansen, I. E., Savage, J. E., Watanabe, K., Bryois, J., Williams, D. M., Steinberg, S., Sealock, J., Karlsson, I. K., Hägg, S., Athanasiu, L., et al. (2019) · Nature Genetics · doi:10.1038/s41588-018-0311-9 · Cited by 2,277
The Immunological Genome Project: networks of gene expression in immune cells
The Immunological Genome Project Consortium, Heng, T. S. P., Painter, M. W., Elpek, K., Lukacs-Kornek, V., Mauermann, N., Turley, S. J., Koller, D., Kim, F. S., Wagers, A. J., et al. (2008) · Nature Immunology · doi:10.1038/ni1008-1091 · Cited by 1,864
Twenty years of the Alzheimer's disease amyloid hypothesis: a genetic perspective
Tanzi, R. E., & Bertram, L. (2005) · Cell · doi:10.1016/j.cell.2005.02.008 · Cited by 1,849
TREM2 Lipid Sensing Sustains the Microglial Response in an Alzheimer’s Disease Model
Wang, Y., Cella, M., Mallinson, K., Ulrich, J. D., Young, K. L., Robinette, M. L., Gilfillan, S., Krishnan, G. M., Sudhakar, S., Zinselmeyer, B. H., et al. (2015) · Cell · doi:10.1016/j.cell.2015.01.049 · Cited by 1,736
Self-citationAlzheimer’s Disease Risk Genes and Mechanisms of Disease Pathogenesis
Karch, C. M., & Goate, A. M. (2015) · Biological Psychiatry · doi:10.1016/j.biopsych.2014.05.006 · Cited by 1,357
TREM2 Maintains Microglial Metabolic Fitness in Alzheimer’s Disease
Ulland, T. K., Song, W. M., Huang, S. C.-C., Ulrich, J. D., Sergushichev, A., Beatty, W. L., Loboda, A. A., Zhou, Y., Cairns, N. J., Kambal, A., et al. (2017) · Cell · doi:10.1016/j.cell.2017.07.023 · Cited by 1,263 · cited 1×
“Given our previous demonstration that TREM2 sustains the mTOR pathway, TREM2 signaling may costimulate preactivated pathways by providing building blocks and energy required for microglial responses to Aβ or other injuries (43).”
BackgroundSelf-citationZhou, Y., Song, W. M., Andhey, P. S., Swain, A., Levy, T., Miller, K. R., Poliani, P. L., Cominelli, M., Grover, S., Gilfillan, S., et al. (2020) · Nature Medicine · doi:10.1038/s41591-019-0695-9 · Cited by 1,150
Self-citationClonally expanded CD8 T cells patrol the cerebrospinal fluid in Alzheimer’s disease
Gate, D., Saligrama, N., Leventhal, O., Yang, A. C., Unger, M. S., Middeldorp, J., Chen, K., Lehallier, B., Channappa, D., De Los Santos, M. B., et al. (2020) · Nature · doi:10.1038/s41586-019-1895-7 · Cited by 992
TREM2-mediated early microglial response limits diffusion and toxicity of amyloid plaques
Wang, Y., Ulland, T. K., Ulrich, J. D., Song, W., Tzaferis, J. A., Hole, J. T., Yuan, P., Mahan, T. E., Shi, Y., Gilfillan, S., et al. (2016) · Journal of Experimental Medicine · doi:10.1084/jem.20151948 · Cited by 840
Self-citationTrajectory-based differential expression analysis for single-cell sequencing data
Van den Berge, K., Roux de Bézieux, H., Street, K., Saelens, W., Cannoodt, R., Saeys, Y., Dudoit, S., & Clement, L. (2020) · Nature Communications · doi:10.1038/s41467-020-14766-3 · Cited by 828
Yuan, P., Condello, C., Keene, C. D., Wang, Y., Bird, T. D., Paul, S. M., Luo, W., Colonna, M., Baddeley, D., & Grutzendler, J. (2016) · Neuron · doi:10.1016/j.neuron.2016.05.003 · Cited by 817
Self-citationTemporal Tracking of Microglia Activation in Neurodegeneration at Single-Cell Resolution
Mathys, H., Adaikkan, C., Gao, F., Young, J. Z., Manet, E., Hemberg, M., De Jager, P. L., Ransohoff, R. M., Regev, A., & Tsai, L.-H. (2017) · Cell Reports · doi:10.1016/j.celrep.2017.09.039 · Cited by 740
TREM2 — a key player in microglial biology and Alzheimer disease
Ulland, T. K., & Colonna, M. (2018) · Nature Reviews Neurology · doi:10.1038/s41582-018-0072-1 · Cited by 735
Self-citationHanna, R. N., Carlin, L. M., Hubbeling, H. G., Nackiewicz, D., Green, A. M., Punt, J. A., Geissmann, F., & Hedrick, C. C. (2011) · Nature Immunology · doi:10.1038/ni.2063 · Cited by 639
Nuclear receptor transrepression pathways that regulate inflammation in macrophages and T cells
Glass, C. K., & Saijo, K. (2010) · Nature Reviews Immunology · doi:10.1038/nri2748 · Cited by 619
Wang, S., Mustafa, M., Yuede, C. M., Salazar, S. V., Kong, P., Long, H., Ward, M., Siddiqui, O., Paul, R., Gilfillan, S., et al. (2020) · Journal of Experimental Medicine · doi:10.1084/jem.20200785 · Cited by 549
Self-citationDisease Progression-Dependent Effects of TREM2 Deficiency in a Mouse Model of Alzheimer's Disease
Jay, T. R., Hirsch, A. M., Broihier, M. L., Miller, C. M., Neilson, L. E., Ransohoff, R. M., Lamb, B. T., & Landreth, G. E. (2017) · The Journal of Neuroscience · doi:10.1523/jneurosci.2110-16.2016 · Cited by 457
Alzheimer’s Patient Microglia Exhibit Enhanced Aging and Unique Transcriptional Activation
Srinivasan, K., Friedman, B. A., Etxeberria, A., Huntley, M. A., van der Brug, M. P., Foreman, O., Paw, J. S., Modrusan, Z., Beach, T. G., Serrano, G. E., et al. (2020) · Cell Reports · doi:10.1016/j.celrep.2020.107843 · Cited by 427
Computational assignment of cell-cycle stage from single-cell transcriptome data
Scialdone, A., Natarajan, K. N., Saraiva, L. R., Proserpio, V., Teichmann, S. A., Stegle, O., Marioni, J. C., & Buettner, F. (2015) · Methods · doi:10.1016/j.ymeth.2015.06.021 · Cited by 409
Lee, C. Y. D., Daggett, A., Gu, X., Jiang, L.-L., Langfelder, P., Li, X., Wang, N., Zhao, Y., Park, C. S., Cooper, Y., et al. (2018) · Neuron · doi:10.1016/j.neuron.2018.02.002 · Cited by 396
Mendez, M. J., Green, L. L., Corvalan, J. R. F., Jia, X.-C., Maynard-Currie, C. E., Yang, X.-D., Gallo, M. L., Louie, D. M., Lee, D. V., Erickson, K. L., et al. (1997) · Nature Genetics · doi:10.1038/ng0297-146 · Cited by 376
Self-citationGreen, L. L., Hardy, M. C., Maynard-Currie, C. E., Tsuda, H., Louie, D. M., Mendez, M. J., Abderrahim, H., Noguchi, M., Smith, D. H., Zeng, Y., et al. (1994) · Nature Genetics · doi:10.1038/ng0594-13 · Cited by 355
Self-citationEnhancing protective microglial activities with a dual function TREM2 antibody to the stalk region
Schlepckow, K., Monroe, K. M., Kleinberger, G., Cantuti‐Castelvetri, L., Parhizkar, S., Xia, D., Willem, M., Werner, G., Pettkus, N., Brunner, B., et al. (2020) · EMBO Molecular Medicine · doi:10.15252/emmm.201911227 · Cited by 324
Otero, K., Turnbull, I. R., Poliani, P. L., Vermi, W., Cerutti, E., Aoshi, T., Tassi, I., Takai, T., Stanley, S. L., Miller, M., et al. (2009) · Nature Immunology · doi:10.1038/ni.1744 · Cited by 315
Self-citationHumanized TREM2 mice reveal microglia-intrinsic and -extrinsic effects of R47H polymorphism
Song, W. M., Joshita, S., Zhou, Y., Ulland, T. K., Gilfillan, S., & Colonna, M. (2018) · Journal of Experimental Medicine · doi:10.1084/jem.20171529 · Cited by 305
Self-citationWunderlich, P., Glebov, K., Kemmerling, N., Tien, N. T., Neumann, H., & Walter, J. (2013) · Journal of Biological Chemistry · doi:10.1074/jbc.m113.517540 · Cited by 296
Beta‐amyloid deposition and the aging brain
Rodrigue, K. M., Kennedy, K. M., & Park, D. C. (2009) · Neuropsychology Review · doi:10.1007/s11065-009-9118-x · Cited by 230
Aβ reduction in BACE1 heterozygous null 5XFAD mice is associated with transgenic APP level
Sadleir, K. R., Eimer, W. A., Cole, S. L., & Vassar, R. (2015) · Molecular Neurodegeneration · doi:10.1186/1750-1326-10-1 · Cited by 213
Thornton, P., Sevalle, J., Deery, M. J., Fraser, G., Zhou, Y., Ståhl, S., Franssen, E. H., Dodd, R. B., Qamar, S., Gomez Perez‐Nievas, B., et al. (2017) · EMBO Molecular Medicine · doi:10.15252/emmm.201707673 · Cited by 200
NR4A nuclear receptors are orphans but not lonesome
Kurakula, K., Koenis, D. S., van Tiel, C. M., & de Vries, C. J. M. (2014) · Biochimica et Biophysica Acta (BBA) - Molecular Cell Research · doi:10.1016/j.bbamcr.2014.06.010 · Cited by 161
Bhattacharya, S., Haertel, C., Maelicke, A., & Montag, D. (2014) · PLoS ONE · doi:10.1371/journal.pone.0089454 · Cited by 142 · cited 3×
“In fact, previous studies have shown that female 5XFAD mice accumulate more Aβ than male 5XFAD mice (27, 28).”
BackgroundInfluentialThe genetic landscape of Alzheimer disease
Carmona, S., Hardy, J., & Guerreiro, R. J. (2018) · Handbook of clinical neurology · doi:10.1016/b978-0-444-64076-5.00026-0 · Cited by 141
Cheng, Q., Danao, J., Talreja, S., Wen, P. H., Yin, J., Sun, N., Li, C.-M., Chui, D., Tran, D. T., Koirala, S., et al. (2018) · Journal of Biological Chemistry · doi:10.1074/jbc.ra118.001848 · Cited by 129
Self-citationThe Nuclear Receptor Nr4a1 Mediates Anti-Inflammatory Effects of Apoptotic Cells
Ipseiz, N., Uderhardt, S., Scholtysek, C., Steffen, M., Schabbauer, G., Bözec, A., Schett, G. A., & Krönke, G. (2014) · The Journal of Immunology · doi:10.4049/jimmunol.1303377 · Cited by 90
Microglia take centre stage in neurodegenerative disease
Heneka, M. T. (2019) · Nature Reviews Immunology · doi:10.1038/s41577-018-0112-5 · Cited by 72
Xu, X., Qiu, C., Zhu, L., Huang, J., Li, L., Fu, W., Zhang, L., Wei, J., Wang, Y., Geng, Y., et al. (2014) · The Journal of Immunology · doi:10.4049/jimmunol.1401249 · Cited by 58
Cited by
TREM2 drives microglia response to amyloid-β via SYK-dependent and -independent pathways
Wang, S., Sudan, R., Peng, V., Zhou, Y., Du, S., Yuede, C. M., Lei, T., Hou, J., Cai, Z., Cella, M., et al. (2022) · Cell · doi:10.1016/j.cell.2022.09.033 · Cited by 471
Self-citationHuman microglial state dynamics in Alzheimer’s disease progression
Sun, N., Victor, M. B., Park, Y. P., Xiong, X., Scannail, A. N., Leary, N., Prosper, S., Viswanathan, S., Luna, X., Boix, C. A., et al. (2023) · Cell · doi:10.1016/j.cell.2023.08.037 · Cited by 462
Colonna, M. (2023) · Nature Reviews Immunology · doi:10.1038/s41577-023-00837-1 · Cited by 394
Self-citationMicroglia in Alzheimer's disease at single-cell level. Are there common patterns in humans and mice?
Chen, Y., & Colonna, M. (2021) · Journal of Experimental Medicine · doi:10.1084/jem.20202717 · Cited by 339
Self-citationMicroglia in Alzheimer’s disease: pathogenesis, mechanisms, and therapeutic potentials
Miao, J., Ma, H., Yang, Y., Liao, Y., Lin, C., Zheng, J., Yu, M., & Lan, J. (2023) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2023.1201982 · Cited by 293
Metadata
- Authors
- 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.
- Affiliations
- Genome Analysis Unit, Amgen Research, Amgen Inc., South San Francisco, CA 94080;
- Department of Pathology and Immunology, Washington University School of Medicine, St Louis, MO 63110;
- Department of Inflammation and Oncology, Amgen Research, Amgen Inc., South San Francisco, CA 94080;
- Department of Biologics Discovery, Amgen Research, Amgen Inc., Burnaby, BC, V5A1V7 Canada;
- Discovery Attribute Sciences, Amgen Research, Amgen Inc., South San Francisco, CA 94080;
- Department of Biologics Optimization, Amgen Research, Amgen Inc., Thousand Oaks, CA 91320;
- Department of Neuroscience, Amgen Research, Amgen Inc., Cambridge, MA 02142;
- Department of Translational Safety and Bioanalytical Sciences, Amgen Research, Amgen Inc., Thousand Oaks, CA 91320.
- ORCID
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2021-01-14
- Volume
- 118
- Issue
- 3
- ISSN
- 0027-8424
- 1091-6490
- Cited by
- 134
- References
- 44
- Language
- en
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 ›
Are you an author, or do you see a problem with this page? Request a review
Data sources
Bibliographic data: Semantic Scholar, OpenAlex, Crossref.
Contains information from the Semantic Scholar Academic Graph Datasets, made available under the ODC Attribution License (ODC-BY 1.0).
Semantic Scholar’s data is described in: Kinney, R., et al. (2023). The Semantic Scholar Open Data Platform. arXiv:2301.10140.
