The DOI matches its Crossref record; 123 of the 123 references it cites were found in a registry or an index.
TREM2 — a key player in microglial biology and Alzheimer disease
Abstract
Alzheimer disease (AD) is a debilitating dementia believed to result from the deposition of extracellular amyloid-β (Aβ)-containing plaques followed by the formation of neurofibrillary tangles. Familial AD typically results from mutations in the genes encoding amyloid precursor protein (APP), presenilin 1 or presenilin 2. Variations in triggering receptor expressed on myeloid cells 2 (TREM2), one of several genes for which expression is restricted to microglia in the brain, have now been shown to increase the risk of developing late-onset AD. Microglia have been shown to respond to Aβ accumulation and neurodegenerative lesions, progressively acquiring a unique transcriptional and functional signature and evolving into disease-associated microglia (DAM). DAM attenuate the progression of neurodegeneration in certain mouse models, but inappropriate DAM activation accelerates neurodegenerative disease in other models. TREM2 is essential for maintaining microglial metabolic fitness during stress events, enabling microglial progression to a fully mature DAM profile and ultimately sustaining the microglial response to Aβ-plaque-induced pathology. Here, we review the current data detailing the role of TREM2 in microglial biology and AD.
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In the citing paper
“TREM2 engagement with ligands triggers the phosphorylation of the DAP12 ITAM, subsequently initiating a cascade of activation of downstream kinases, such as AKT, MAPK, and mTOR29,30.”
From TREM2 promotes lung fibrosis via controlling alveolar macrophage survival and pro-fibrotic activity (2025) · cites this paper as [30]
In the citing paper
“These kinases are centrally involved in controlling cell metabolism, survival, proliferation, and phagocytosis29,30.”
From TREM2 promotes lung fibrosis via controlling alveolar macrophage survival and pro-fibrotic activity (2025) · cites this paper as [30]
In the citing paper
“TREM2 engagement leads to DAP12 phosphorylation, followed by recruitment and activation of the spleen-associated tyrosine kinase (SYK), resulting in downstream signaling events leading to proliferation, survival, phagocytosis, and secretion of cytokines and chemokines [47].”
From TREM2 activation on microglia promotes myelin debris clearance and remyelination in a model of multiple sclerosis (2020) · cites this paper as [47]
In the citing paper
“The general consensus is that TREM2 is expressed by microglia in the CNS, especially after activation [6, 21, 47].”
From TREM2 activation on microglia promotes myelin debris clearance and remyelination in a model of multiple sclerosis (2020) · cites this paper as [47]
In the citing paper
“TREM2 binds on the membrane to the DNAX-activation protein 12 (DAP12) which is an adaptor protein required for TREM2 surface expression and intracellular signaling [47].”
From TREM2 activation on microglia promotes myelin debris clearance and remyelination in a model of multiple sclerosis (2020) · cites this paper as [47]
In the citing paper
“In comparison to previous studies which are aligned to the concept that suppressing microglial function may be beneficial in the setting of AD [49], the data described here, together with studies on TREM2 and other AD-associated variants, suggest that a different directionality may be therapeutically useful [6, 46, 50].”
From Alzheimer’s disease phospholipase C-gamma-2 (PLCG2) protective variant is a functional hypermorph (2019) · cites this paper as [46]
In the citing paper
“One receptor acting upstream of Plcg2 and evoking such responses in innate immune cells might be Trem2 [17, 46].”
From Alzheimer’s disease phospholipase C-gamma-2 (PLCG2) protective variant is a functional hypermorph (2019) · cites this paper as [46]
In the citing paper
“TREM2 is one of the key receptors modulating PLCγ2 activity [12, 36, 37].”
From Protective PLCG2 variants associate with a delayed onset of Alzheimer’s disease among heterozygous APOE ε4 carriers (2026) · cites this paper as [36]
In the citing paper
“Although TREM2 is expressed on the cell surface, it is cleaved from the cell surface by metalloproteases and released as soluble TREM2 (sTREM2) (Ulland and Colonna, 2018).”
From TREM2 Modulation Remodels the Tumor Myeloid Landscape Enhancing Anti-PD-1 Immunotherapy (2020) · cites this paper as Ulland and Colonna, 2018
In the citing paper
“TREM2 has been extensively studied in microglia for its capacity to sustain microglial responses to neurodegenerative pathologies such as Alzheimer’s disease (Ulland and Colonna, 2018).”
From TREM2 Modulation Remodels the Tumor Myeloid Landscape Enhancing Anti-PD-1 Immunotherapy (2020) · cites this paper as Ulland and Colonna, 2018
In the citing paper
“This could be representative of changes in TREM2 expression or shedding, both of which are altered during ageing and disease [55], thereby reducing TREM2-mediated signalling and subsequent conversion of microglia to DAM [56].”
From TREM2/PLCγ2 signalling in immune cells: function, structural insight, and potential therapeutic modulation (2021) · cites this paper as [56]
In the citing paper
“Rac is known to be activated downstream of TREM2/DAP12 via Syk and Vav2/3 activation [56].”
From TREM2/PLCγ2 signalling in immune cells: function, structural insight, and potential therapeutic modulation (2021) · cites this paper as [56]
In the citing paper
“Mutations affecting the TREM2 function impair microglial activation (37) and reduce their ability to accumulate LDs in the AD brain (38).”
From Reducing microglial lipid load enhances β amyloid phagocytosis in an Alzheimer’s disease mouse model (2025) · cites this paper as [37]
In the citing paper
“Loss-of-function (LOF) variants of TREM2, an immune receptor expressed in microglia, increase Alzheimer’s disease risk.”
From TREM2 regulates microglial cholesterol metabolism upon chronic phagocytic challenge (2020) · cites this paper as Ulland and Colonna, 2018
In the citing paper
“Certain TREM2 LOAD variants, including R47H, show reduced affinity to lipids”
From TREM2 regulates microglial cholesterol metabolism upon chronic phagocytic challenge (2020) · cites this paper as Ulland and Colonna, 2018
In the citing paper
“Most notably, a hypomorphic variant in the microglial receptor TREM2, R47H, increases the risk of AD several fold, as do other TREM2 variants, such as R62H, although with reduced penetrance14.”
From Human and mouse single-nucleus transcriptomics reveal TREM2-dependent and TREM2-independent cellular responses in Alzheimer’s disease (2020) · cites this paper as [14]
In the citing paper
“AD patients carrying the R47H variant, who have a higher risk (2-4-fold) of developing AD than do R62H carriers.”
From Human and mouse single-nucleus transcriptomics reveal TREM2-dependent and TREM2-independent cellular responses in Alzheimer’s disease (2020) · cites this paper as [14]
Citations
Cites
Corder, E. H., Saunders, A. M., Strittmatter, W. J., Schmechel, D. E., Gaskell, P. C., Small, G. W., Roses, A. D., Haines, J. L., & Pericak-Vance, M. A. (1993) · Science · doi:10.1126/science.8346443 · Cited by 9,429
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-citation2016 Alzheimer's disease facts and figures
Alzheimer's Association (2016) · Alzheimer's & Dementia · doi:10.1016/j.jalz.2016.03.001 · Cited by 5,069
Goate, A., Chartier-Harlin, M.-C., Mullan, M., Brown, J., Crawford, F., Fidani, L., Giuffra, L., Haynes, A., Irving, N., James, L., et al. (1991) · Nature · doi:10.1038/349704a0 · Cited by 4,659
Meta-Analysis of 74,046 Individuals Identifies 11 New Susceptibility Loci for Alzheimer’s Disease
(EADI), E. A. D. I., Lambert, J.-C., (GERAD), G. A. E. R. I. A. D., Alzheimer's Disease Genetic Consortium (ADGC), (CHARGE), C. F. H. A. A. R. I. G. E., Ibrahim-Verbaas, C. A., Harold, D., Naj, A. C., Sims, R., Bellenguez, C., et al. (2013) · Nature Genetics · doi:10.1038/ng.2802 · Cited by 4,336
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
Synaptic Pruning by Microglia Is Necessary for Normal Brain Development
Paolicelli, R. C., Bolasco, G., Pagani, F., Maggi, L., Scianni, M., Panzanelli, P., Giustetto, M., Ferreira, T. A., Guiducci, E., Dumas, L., et al. (2011) · Science · doi:10.1126/science.1202529 · Cited by 4,244
Microglia Sculpt Postnatal Neural Circuits in an Activity and Complement-Dependent Manner
Schafer, D. P., Lehrman, E. K., Kautzman, A. G., Koyama, R., Mardinly, A. R., Yamasaki, R., Ransohoff, R. M., Greenberg, M. E., Barres, B. A., & Stevens, B. (2012) · Neuron · doi:10.1016/j.neuron.2012.03.026 · Cited by 4,089
Cloning of a gene bearing missense mutations in early-onset familial Alzheimer's disease
Sherrington, R., Rogaev, E. I., Liang, Y., Rogaeva, E. A., Levesque, G., Ikeda, M., Chi, H., Lin, C., Li, G., Holman, K., et al. (1995) · Nature · doi:10.1038/375754a0 · Cited by 4,051
Complement and microglia mediate early synapse loss in Alzheimer mouse models
Hong, S., Beja-Glasser, V. F., Nfonoyim, B. M., Frouin, A., Li, S., Ramakrishnan, S., Merry, K. M., Shi, Q., Rosenthal, A., Barres, B. A., et al. (2016) · Science · doi:10.1126/science.aad8373 · Cited by 3,343
Research works printed but not linked: 3
- Nissl, F. in Histologische und histopathologische Arbeiten über die Grosshirnrinde Vol. 1 (eds. Nissl, F., Alzheimer, A.) 315–494 (G. Fischer, Jena, Germany, 1904).
- Alzheimer, A. in Histologische und histopathologische Arbeiten über die Grosshirnrinde Vol. 3 (eds. Nissl, F., Alzheimer, A.) 401–562 (G. Fischer, Jena, Germany, 1910).
- Hortega, P. R. El tercer elemento de los centros nerviosos. III. Naturaleza probable de la microglía [Spanish]. Bol. Soc. Esp. Biol. 8, 108–115 (1919).
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Lagni, A., Lotti, V., Diani, E., Cecchetto, R., Turrina, S., Raniero, D., Palmisano, A., Mazzariol, A., Gibellini, D., & Paolone, G. (2026) · Current Issues in Molecular Biology · doi:10.3390/cimb48080750
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Roy, J., Tsui, K. C., Poon, C. H., Zhang, J., Lai, Y., Wong, K. Y., Mihardja, M., Tse, V., Li, P. C., Au, C., et al. (2026) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2026.107077
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Metadata
- Authors
- Ulland, T. K., & Colonna, M.
- Affiliations
- University of Wisconsin–Madison (US)
- Washington University in St. Louis (US)
- Corresponding author
- Colonna, Marco
- Venue
- Nature Reviews Neurology
- Published
- 2018-09-28
- Volume
- 14
- Issue
- 11
- Pages
- 667-675
- ISSN
- 1759-4758 (ISSN-L)
- 1759-4766
- OpenAlex
- W2894203109
- Semantic Scholar
- ee2227720d29d3e454a2aa0cfa8d9df4c32b869a
- Cited by
- 735
- References
- 123
- Citations by year
- 2026: 102 · 2025: 115 · 2024: 119 · 2023: 100 · 2022: 117 · 2021: 89 · 2020: 60 · 2019: 29 · 2018: 3
- FWCI
- 4.28
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Reviews Neurology (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Inflammasome and immune disorders
- Keywords
- TREM2, Alzheimer's disease, microglia, disease-associated microglia, amyloid plaques, neuroinflammation, late-onset Alzheimer's disease, neurodegeneration
- MeSH terms
- Alzheimer Disease, Animals, Humans, Membrane Glycoproteins, Mutation, Receptors, Immunologic, Amyloid beta-Protein Precursor, Microglia, Presenilins
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