The DOI matches its Crossref record; 22 of the 22 references it cites were found in a registry or an index.
Alzheimer's disease‐associated TREM2 variants exhibit either decreased or increased ligand‐dependent activation
Open accessAbstract
Introduction: TREM2 is a lipid‐sensing activating receptor on microglia known to be important for Alzheimer's disease (AD), but whether it plays a beneficial or detrimental role in disease pathogenesis is controversial. Methods: We analyzed AD risk of TREM2 variants in the NIMH AD Genetics Initiative Study and AD Sequencing Project. We compared each variant's risk and functional impact by a reporter assay. Finally, we analyzed expression of TREM2 on human monocytes. Results: We provide more evidence for increased AD risk associated with several TREM2 variants, and show that these variants decreased or markedly increased binding to TREM2 ligands. We identify HDL and LDL as novel TREM2 ligands. We also show that TREM2 expression in human monocytes is minimal compared to monocyte‐derived dendritic cells. Discussion: Our results suggest that TREM2 signaling helps protect against AD but can cause harm in excess, supporting the idea that proper TREM2 function is important to counteract disease progression.
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“The most characterised variant of TREM2 (p.R47H) shows defects in ligand binding [6, 37, 38, 97], which impacts the ability of TREM2 to recognise damage, and induce microglial changes, resulting in a dampened response to pathological insults such as Aβ deposition.”
From TREM2/PLCγ2 signalling in immune cells: function, structural insight, and potential therapeutic modulation (2021) · cites this paper as [97]
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In the citing paper
“such as reduced ligand binding (p.R47H [96], p.R62H [97])”
From TREM2/PLCγ2 signalling in immune cells: function, structural insight, and potential therapeutic modulation (2021) · cites this paper as [97]
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In the citing paper
“A number of mutations in PLCG2 (about 75%), that have been previously implicated in various inflammatory diseases [92–102], actually map to the autoinhibitory interface on the PLCγ2 model structure and can be considered as pathogenic (Fig. 2c)”
From TREM2/PLCγ2 signalling in immune cells: function, structural insight, and potential therapeutic modulation (2021) · cites this paper as [97]
Experimental — accuracy not yet measuredIn the citing paper
“TREM2 binds polyanions, particularly phospholipids and sulfatides that may be exposed in the brain during Aβ accumulation due to neuronal cell apoptosis and myelin damage (114).”
From Microglia Function in the Central Nervous System During Health and Neurodegeneration (2017) · cites this paper as [115]
In the citing paper
“In the initial week following injury, the microglia population adopts a balanced distribution between pro- and anti-inflammatory states to promote neurogenesis and enhance the immune response to injury [89,110,111].”
From Untangling senescent and damage‐associated microglia in the aging and diseased brain (2023) · cites this paper as [89]
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Strittmatter, W. J., Saunders, A. M., Schmechel, D., Pericak-Vance, M., Enghild, J., Salvesen, G. S., & Roses, A. D. (1993) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.90.5.1977 · Cited by 4,268
Harold, D., Abraham, R., Hollingworth, P., Sims, R., Gerrish, A., Hamshere, M. L., Pahwa, J. S., Moskvina, V., Dowzell, K., Williams, A., et al. (2009) · Nature Genetics · doi:10.1038/ng.440 · Cited by 3,326
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
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
Genome-wide association study identifies variants at CLU and CR1 associated with Alzheimer's disease
the European Alzheimer's Disease Initiative Investigators, Lambert, J.-C., Heath, S., Even, G., Campion, D., Sleegers, K., Hiltunen, M., Combarros, O., Zelenika, D., Bullido, M. J., et al. (2009) · Nature Genetics · doi:10.1038/ng.439 · Cited by 2,234
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-citationInnate immunity in Alzheimer's disease
Heneka, M. T., Golenbock, D. T., & Latz, E. (2015) · Nature Immunology · doi:10.1038/ni.3102 · Cited by 902
TREM2 mutations implicated in neurodegeneration impair cell surface transport and phagocytosis
Kleinberger, G., Yamanishi, Y., Suárez-Calvet, M., Czirr, E., Lohmann, E., Cuyvers, E., Struyfs, H., Pettkus, N., Wenninger-Weinzierl, A., Mazaheri, F., et al. (2014) · Science Translational Medicine · doi:10.1126/scitranslmed.3009093 · Cited by 798
Self-citationJay, T. R., Miller, C. M., Cheng, P. J., Graham, L. C., Bemiller, S., Broihier, M. L., Xu, G., Margevicius, D., Karlo, J. C., Sousa, G. L., et al. (2015) · Journal of Experimental Medicine · doi:10.1084/jem.20142322 · Cited by 682 · cited 1×
“However, mixed results were reported with regard to plaque burden [7,8], and therefore, as with microglia in general, it is not settled whether TREM2 plays a beneficial or detrimental role in the context of AD.”
ResultApolipoprotein E Is a Ligand for Triggering Receptor Expressed on Myeloid Cells 2 (TREM2)
Atagi, Y., Liu, C.-C., Painter, M. M., Chen, X.-F., Verbeeck, C., Zheng, H., Li, X., Rademakers, R., Kang, S. S., Xu, H., et al. (2015) · Journal of Biological Chemistry · doi:10.1074/jbc.m115.679043 · Cited by 587
Cited by
Sorted by citations
Items 101–109 of 109
Singh, A. K., Mishra, G., Maurya, A., Awasthi, R., Kumari, K., Thakur, A., Rai, A., Rai, G. K., Sharma, B., Kulkarni, G. T., et al. (2019) · Current Alzheimer Research · doi:10.2174/1567205016666190903102822 · Cited by 45
Li, R., Wang, X., & He, P. (2021) · Experimental and Therapeutic Medicine · doi:10.3892/etm.2021.9778 · Cited by 39
INPP5D modulates TREM2 loss-of-function phenotypes in a β-amyloidosis mouse model
Iguchi, A., Takatori, S., Kimura, S., Muneto, H., Wang, K., Etani, H., Ito, G., Sato, H., Hori, Y., Sasaki, J., et al. (2023) · iScience · doi:10.1016/j.isci.2023.106375 · Cited by 37
Olive, C., Ibanez, L., Farias, F. H. G., Wang, F., Budde, J. P., Norton, J. B., Gentsch, J., Morris, J. C., Li, Z., Dube, U., et al. (2020) · Journal of Alzheimer’s Disease · doi:10.3233/jad-200019 · Cited by 32
Llibre-Guerra, J. J., Fernandez, M. V., Joseph-Mathurin, N., Bian, S., Carter, K., Li, Y., Aschenbrenner, A. J., Pottier, C., Sigurdson, W., McDade, E., et al. (2025) · Nature Medicine · doi:10.1038/s41591-025-03494-0 · Cited by 28
Self-citationVarnum, M. M., Clayton, K. A., Yoshii-Kitahara, A., Yonemoto, G., Koro, L., Ikezu, S., & Ikezu, T. (2017) · Journal of Biological Chemistry · doi:10.1074/jbc.m116.759159 · Cited by 22
Novel approaches to increase synaptic resilience as potential treatments for Alzheimer’s disease
Pham, A. Q., & Dore, K. (2023) · Seminars in Cell & Developmental Biology · doi:10.1016/j.semcdb.2022.03.032 · Cited by 21
TREM2 risk variants and associated endophenotypes in alzheimer’s disease
Dijkstra, J. I. R., Vermunt, L., Venkatraghavan, V., Ozhegov, G., Coomans, E. M., Ossenkoppele, R., van de Giessen, E., Hulsman, M., de Geus, C. M., van der Flier, W. M., et al. (2025) · Alzheimer's Research & Therapy · doi:10.1186/s13195-025-01700-2 · Cited by 18
TREM2-dependent senescent microglia conserved in aging and Alzheimer’s disease
Rachmian, N., Medina, S., Cherqui, U., Akiva, H., Deitch, D., Edilbi, D., Croese, T., Salame, T., Peralta Ramos, J., Cahalon, L., et al. (2023) · doi:10.1101/2023.03.20.533401 · Cited by 6
Metadata
- Authors
- Song, W., Hooli, B., Mullin, K., Jin, S. C., Cella, M., Ulland, T. K., Wang, Y., Tanzi, R. E., & Colonna, M.
- Affiliations
- Washington University in St. Louis (US)
- Harvard University (US)
- Yale University (US)
- Corresponding author
- Tanzi, Rudolph E.
- Colonna, Marco
- ORCID
- Venue
- Alzheimer's & Dementia
- Publisher
- Wiley
- Published
- 2016-08-09
- Volume
- 13
- Issue
- 4
- Pages
- 381-387
- ISSN
- 1552-5260 (ISSN-L)
- 1552-5279
- PMC
- PMC5299056
- OpenAlex
- W2500839489
- Cited by
- 297
- References
- 22
- Citations by year
- 2026: 15 · 2025: 36 · 2024: 22 · 2023: 65 · 2022: 45 · 2021: 31 · 2020: 22 · 2019: 20 · 2018: 26 · 2017: 13 · 2016: 2
- FWCI
- 11.14
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Alzheimer s & Dementia (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Eli Lilly and Company
- National Institute of Mental Health (5R01MH060009‐14)
- JPB Foundation (RG4687A1/1)
- National Multiple Sclerosis Society
- Cure Alzheimer's Fund
- Topics
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Keywords
- TREM2, Alzheimer's disease
- MeSH terms
- Alzheimer Disease, Cells, Cultured, Family, Humans, Lipoproteins, HDL, Lipoproteins, LDL, Membrane Glycoproteins, Monocytes, Protein Binding, Receptors, Immunologic, Genetic Variation, Cohort Studies, Logistic Models, Genetic Predisposition to Disease, Genetic Association Studies
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