TREM2 — a key player in microglial biology and Alzheimer disease

Ulland, Tyler K.; Colonna, Marco

doi:10.1038/s41582-018-0072-1

Cited by 737Neuroinflammation and Neurodegeneration MechanismsAlzheimer's disease research and treatmentsInflammasome and immune disorders

TREM2 — a key player in microglial biology and Alzheimer disease

Ulland, Tyler K., Colonna, Marco·2018·Nature Reviews Neurology

DOI 10.1038/s41582-018-0072-1

Open this paper in CoChat — free account

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.

Integrity signals

Registry

Crossref · 10.1038/s41582-018-0072-1

Cites

123 of 123 references verified0 citation errors · 0 not checkable

Statistics

Recomputing p-values needs the paper’s full text.

Claims the paper makes

This paper’s full text isn’t openly available, so its claims and self-check weren’t run. The registry and citation checks still apply.

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?

TREM2 engagement with ligands triggers phosphorylation of DAP12 ITAM and activates downstream kinases such as AKT, MAPK, and mTOR.
“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]
These kinases are centrally involved in controlling cell metabolism, survival, proliferation, and phagocytosis.
“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]
TREM2 engagement leads to DAP12 phosphorylation, followed by recruitment and activation of SYK, resulting in downstream signaling events leading to proliferation, survival, phagocytosis, and secretion of cytokines and chemokines.
“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]
TREM2 is expressed by microglia in the CNS, especially after activation.
“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]
TREM2 binds on the membrane to DAP12, an adaptor protein required for TREM2 surface expression and intracellular signaling.
“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]

The data suggest that a different directionality (activating rather than suppressing microglia) may be therapeutically useful in AD.
“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]
Trem2 might be one receptor acting upstream of Plcg2 and evoking such responses in innate immune cells.
“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]
TREM2 is one of the key receptors modulating PLCγ2 activity.
“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]
TREM2 is cleaved from the cell surface by metalloproteases and released as soluble TREM2 (sTREM2).
“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
TREM2 sustains microglial responses to neurodegenerative pathologies such as Alzheimer's disease.
“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
This could be representative of changes in TREM2 expression or shedding, both of which are altered during ageing and disease, thereby reducing TREM2-mediated signalling and subsequent conversion of microglia to DAM.
“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]
Rac is known to be activated downstream of TREM2/DAP12 via Syk and Vav2/3 activation.
“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]
TREM2 mutations impair microglial activation and reduce their ability to accumulate lipid droplets in the AD brain.
“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]
Variants in TREM2, including R47H and R62H, raise the risk of Alzheimer's disease.
“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]
The R47H variant carries a higher risk of developing Alzheimer's disease, about 2-4-fold, than R62H.
“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]

Gene Dose of Apolipoprotein E Type 4 Allele and the Risk of Alzheimer's Disease in Late Onset Families
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 · see citing works
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 · see citing works
Self-citation
2016 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 · see citing works
Segregation of a missense mutation in the amyloid precursor protein gene with familial Alzheimer's disease
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 · see citing works
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 · see citing works
Apolipoprotein E: high-avidity binding to beta-amyloid and increased frequency of type 4 allele in late-onset familial Alzheimer disease.
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 · see citing works
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 · see citing works
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 · see citing works
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 · see citing works
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 · see citing works
Genome-wide association study identifies variants at CLU and PICALM associated with Alzheimer's disease
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 · see citing works
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 · see citing works
NLRP3 is activated in Alzheimer’s disease and contributes to pathology in APP/PS1 mice
Heneka, M. T., Kummer, M. P., Stutz, A., Delekate, A., Schwartz, S., Vieira-Saecker, A., Griep, A., Axt, D., Remus, A., Tzeng, T.-C., et al. (2013) · Nature · doi:10.1038/nature11729 · Cited by 2,898 · see citing works
Microglia promote learning-dependent synapse formation through brain-derived neurotrophic factor
Parkhurst, C. N., Yang, G., Ninan, I., Savas, J. N., Yates, J. R., Lafaille, J. J., Hempstead, B. L., Littman, D. R., & Gan, W.-B. (2013) · Cell · doi:10.1016/j.cell.2013.11.030 · Cited by 2,599 · see citing works
Identification of a unique TGF-β–dependent molecular and functional signature in microglia
Butovsky, O., Jedrychowski, M. P., Moore, C. S., Cialic, R., Lanser, A. J., Gabriely, G., Koeglsperger, T., Dake, B., Wu, P. M., Doykan, C. E., et al. (2014) · Nature Neuroscience · doi:10.1038/nn.3599 · Cited by 2,579 · see citing works
Candidate gene for the chromosome 1 familial Alzheimer’s disease locus
Levy-Lahad, E., Wasco, W., Poorkaj, P., Romano, D. M., Oshima, J., Pettingell, W. H., Yu, C.-E., Jondro, P. D., Schmidt, S. D., Wang, K., et al. (1995) · Science · doi:10.1126/science.7638622 · Cited by 2,577 · see citing works
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 · see citing works
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 · see citing works
Familial Alzheimer's disease in kindreds with missense mutations in a gene on chromosome 1 related to the Alzheimer's disease type 3 gene
Rogaev, E. I., Sherrington, R., Rogaeva, E. A., Levesque, G., Ikeda, M., Liang, Y., Chi, H., Lin, C., Holman, K., Tsuda, T., et al. (1995) · Nature · doi:10.1038/376775a0 · Cited by 2,052 · see citing works
Common variants at ABCA7, MS4A6A/MS4A4E, EPHA1, CD33 and CD2AP are associated with Alzheimer's disease
Initiative, T. A. D. N., Hollingworth, P., CHARGE consortium, EADI1 consortium, Harold, D., Sims, R., Gerrish, A., Lambert, J.-C., Carrasquillo, M. M., Abraham, R., et al. (2011) · Nature Genetics · doi:10.1038/ng.803 · Cited by 1,997 · see citing works
Common variants at MS4A4/MS4A6E, CD2AP, CD33 and EPHA1 are associated with late-onset Alzheimer's disease
Naj, A. C., Jun, G., Beecham, G. W., Wang, L.-S., Vardarajan, B. N., Buros, J., Gallins, P. J., Buxbaum, J. D., Jarvik, G. P., Crane, P. K., et al. (2011) · Nature Genetics · doi:10.1038/ng.801 · Cited by 1,901 · see citing works
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 · see citing works
Self-citation
Disease-Associated Microglia: A Universal Immune Sensor of Neurodegeneration
Deczkowska, A., Keren-Shaul, H., Weiner, A., Colonna, M., Schwartz, M., & Amit, I. (2018) · Cell · doi:10.1016/j.cell.2018.05.003 · Cited by 1,474 · see citing works
Self-citation
Alzheimer’s Disease: The Challenge of the Second Century
Holtzman, D. M., Morris, J. C., & Goate, A. M. (2011) · Science Translational Medicine · doi:10.1126/scitranslmed.3002369 · Cited by 1,424 · see citing works
Mutation of the Alzheimer's Disease Amyloid Gene in Hereditary Cerebral Hemorrhage, Dutch Type
Levy, E., Carman, M. D., Fernandez-Madrid, I. J., Power, M. D., Lieberburg, I. M., van Duinen, S. G., Bots, G. T. A. M., Luyendijk, W., & Frangione, B. (1990) · Science · doi:10.1126/science.2111584 · Cited by 1,380 · see citing works
Cutting edge: inflammatory responses can be triggered by TREM-1, a novel receptor expressed on neutrophils and monocytes
Bouchon, A., Dietrich, J., & Colonna, M. (2000) · The Journal of Immunology · doi:10.4049/jimmunol.164.10.4991 · Cited by 1,284 · see citing works
Self-citation
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 · see citing works
Self-citation
An environment-dependent transcriptional network specifies human microglia identity
Gosselin, D., Skola, D., Coufal, N. G., Holtman, I. R., Schlachetzki, J. C. M., Sajti, E., Jaeger, B. N., O’Connor, C., Fitzpatrick, C., Pasillas, M. P., et al. (2017) · Science · doi:10.1126/science.aal3222 · Cited by 1,252 · see citing works
Genome-wide Analysis of Genetic Loci Associated With Alzheimer Disease
Seshadri, S. (2010) · JAMA · doi:10.1001/jama.2010.574 · Cited by 1,219 · see citing works
Microglia development follows a stepwise program to regulate brain homeostasis
Matcovitch-Natan, O., Winter, D. R., Giladi, A., Vargas Aguilar, S., Spinrad, A., Sarrazin, S., Ben-Yehuda, H., David, E., Zelada González, F., Perrin, P., et al. (2016) · Science · doi:10.1126/science.aad8670 · Cited by 1,180 · see citing works
The Genetic Defect Causing Familial Alzheimer's Disease Maps on Chromosome 21
George‐Hyslop, P. S., Tanzi, R. E., Polinsky, R. J., Haines, J. L., Nee, L. E., Watkins, P. C., Myers, R. H., Feldman, R. G., Pollen, D. A., Drachman, D. A., et al. (1987) · Science · doi:10.1126/science.2880399 · Cited by 1,160 · see citing works
Rare coding variants in PLCG2, ABI3, and TREM2 implicate microglial-mediated innate immunity in Alzheimer's disease
ARUK Consortium, Sims, R., GERAD/PERADES, C., van der Lee, S. J., Naj, A. C., Bellenguez, C., Badarinarayan, N., Jakobsdottir, J., Kunkle, B. W., Boland, A., et al. (2017) · Nature Genetics · doi:10.1038/ng.3916 · Cited by 1,126 · see citing works
Debris clearance by microglia: an essential link between degeneration and regeneration
Neumann, H., Kotter, M. R., & Franklin, R. J. M. (2008) · Brain · doi:10.1093/brain/awn109 · Cited by 1,111 · see citing works
Alzheimer’s Disease Risk Gene CD33 Inhibits Microglial Uptake of Amyloid Beta
Griciuc, A., Serrano-Pozo, A., Parrado, A. R., Lesinski, A. N., Asselin, C. N., Mullin, K., Hooli, B., Choi, S. H., Hyman, B. T., & Tanzi, R. E. (2013) · Neuron · doi:10.1016/j.neuron.2013.04.014 · Cited by 1,004 · see citing works
Microglia-derived ASC specks cross-seed amyloid-β in Alzheimer’s disease
Venegas, C., Kumar, S., Franklin, B. S., Dierkes, T., Brinkschulte, R., Tejera, D., Vieira-Saecker, A., Schwartz, S., Santarelli, F., Kummer, M. P., et al. (2017) · Nature · doi:10.1038/nature25158 · Cited by 983 · see citing works
TREM2 Binds to Apolipoproteins, Including APOE and CLU/APOJ, and Thereby Facilitates Uptake of Amyloid-Beta by Microglia
Yeh, F. L., Wang, Y., Tom, I., Gonzalez, L. C., & Sheng, M. (2016) · Neuron · doi:10.1016/j.neuron.2016.06.015 · Cited by 943 · see citing works
Microglia activated by IL-4 or IFN-γ differentially induce neurogenesis and oligodendrogenesis from adult stem/progenitor cells
Butovsky, O., Ziv, Y., Schwartz, A., Landa, G., Talpalar, A. E., Pluchino, S., Martino, G., & Schwartz, M. (2006) · Molecular and Cellular Neuroscience · doi:10.1016/j.mcn.2005.10.006 · Cited by 923 · see citing works
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 · see citing works
Self-citation
TREM2 Haplodeficiency in Mice and Humans Impairs the Microglia Barrier Function Leading to Decreased Amyloid Compaction and Severe Axonal Dystrophy
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 · see citing works
Self-citation
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 · see citing works
Self-citation
P1‐146: Chlamydia Pneumoniae‐Infected Astrocytes Alter Their Expression of Adam10, Bace1, and Presenilin‐1 Proteases
Al-Atrache, Z., Cader, A., & Appelt, D. M. (2016) · Alzheimer s & Dementia · doi:10.1016/j.jalz.2016.06.894 · Cited by 765 · see citing works
TREM2 Is a Receptor for β-Amyloid that Mediates Microglial Function
Zhao, Y., Wu, X., Li, X., Jiang, L.-L., Gui, X., Liu, Y., Sun, Y., Zhu, B., Piña-Crespo, J. C., Zhang, M., et al. (2018) · Neuron · doi:10.1016/j.neuron.2018.01.031 · Cited by 763 · see citing works
Temporal 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 · see citing works
Microglia constitute a barrier that prevents neurotoxic protofibrillar Aβ42 hotspots around plaques
Condello, C., Yuan, P., Schain, A., & Grutzendler, J. (2015) · Nature Communications · doi:10.1038/ncomms7176 · Cited by 718 · see citing works
Eliminating microglia in Alzheimer’s mice prevents neuronal loss without modulating amyloid-β pathology
Spangenberg, E. E., Lee, R. J., Najafi, A. R., Rice, R. A., Elmore, M. R. P., Blurton-Jones, M., West, B. L., & Green, K. N. (2016) · Brain · doi:10.1093/brain/aww016 · Cited by 700 · see citing works
Cutting Edge: TREM-2 Attenuates Macrophage Activation
Turnbull, I. R., Gilfillan, S., Cella, M., Aoshi, T., Miller, M., Piccio, L., Hernandez, M., & Colonna, M. (2006) · The Journal of Immunology · doi:10.4049/jimmunol.177.6.3520 · Cited by 688 · see citing works
Self-citation
Mutations in Two Genes Encoding Different Subunits of a Receptor Signaling Complex Result in an Identical Disease Phenotype
Paloneva, J., Manninen, T., Christman, G., Hovanes, K., Mandelin, J., Adolfsson, R., Bianchin, M., Bird, T., Miranda, R., Salmaggi, A., et al. (2002) · The American Journal of Human Genetics · doi:10.1086/342259 · Cited by 683 · see citing works
TREM2 deficiency eliminates TREM2+ inflammatory macrophages and ameliorates pathology in Alzheimer’s disease mouse models
Jay, 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 · see citing works
A Neurodegeneration-Specific Gene-Expression Signature of Acutely Isolated Microglia from an Amyotrophic Lateral Sclerosis Mouse Model
Chiu, I. M., Morimoto, E. T. A., Goodarzi, H., Liao, J. T., O’Keeffe, S., Phatnani, H. P., Muratet, M., Carroll, M. C., Levy, S., Tavazoie, S., et al. (2013) · Cell Reports · doi:10.1016/j.celrep.2013.06.018 · Cited by 651 · see citing works
Apolipoprotein 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 · see citing works
CD33 Alzheimer's disease locus: altered monocyte function and amyloid biology
Initiative, T. A. D. N., Bradshaw, E. M., Chibnik, L. B., Keenan, B. T., Ottoboni, L., Raj, T., Tang, A., Rosenkrantz, L. L., Imboywa, S., Lee, M., et al. (2013) · Nature Neuroscience · doi:10.1038/nn.3435 · Cited by 570 · see citing works
Anti-Amyloid-β Monoclonal Antibodies for Alzheimer’s Disease: Pitfalls and Promise
van Dyck, C. H. (2018) · Biological Psychiatry · doi:10.1016/j.biopsych.2017.08.010 · Cited by 568 · see citing works
TREM2 sustains microglial expansion during aging and response to demyelination
Poliani, P. L., Wang, Y., Fontana, E., Robinette, M. L., Yamanishi, Y., Gilfillan, S., & Colonna, M. (2015) · Journal of Clinical Investigation · doi:10.1172/jci77983 · Cited by 525 · see citing works
Self-citation
sTREM2 cerebrospinal fluid levels are a potential biomarker for microglia activity in early‐stage Alzheimer's disease and associate with neuronal injury markers
Suárez‐Calvet, M., Kleinberger, G., Araque Caballero, M. Á., Brendel, M., Rominger, A., Alcolea, D., Fortea, J., Lleó, A., Blesa, R., Gispert, J. D., et al. (2016) · EMBO Molecular Medicine · doi:10.15252/emmm.201506123 · Cited by 522 · see citing works
TREM2 deficiency attenuates neuroinflammation and protects against neurodegeneration in a mouse model of tauopathy
Leyns, C. E. G., Ulrich, J. D., Finn, M. B., Stewart, F. R., Koscal, L. J., Remolina Serrano, J., Robinson, G. O., Anderson, E., Colonna, M., & Holtzman, D. M. (2017) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1710311114 · Cited by 517 · see citing works
Self-citation
Genome-wide Association Analysis Reveals Putative Alzheimer's Disease Susceptibility Loci in Addition to APOE
Bertram, L., Lange, C., Mullin, K., Parkinson, M., Hsiao, M., Hogan, M. F., Schjeide, B. M. M., Hooli, B., DiVito, J., Ionita, I., et al. (2008) · The American Journal of Human Genetics · doi:10.1016/j.ajhg.2008.10.008 · Cited by 511 · see citing works
A role for TREM2 ligands in the phagocytosis of apoptotic neuronal cells by microglia
Hsieh, C. L., Koike, M., Spusta, S. C., Niemi, E. C., Yenari, M., Nakamura, M. C., & Seaman, W. E. (2009) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2009.06042.x · Cited by 475 · see citing works
Alzheimer’s Disease Genetics: From the Bench to the Clinic
Karch, C. M., Cruchaga, C., & Goate, A. M. (2014) · Neuron · doi:10.1016/j.neuron.2014.05.041 · Cited by 473 · see citing works
Disease 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 · see citing works
TREM2- and DAP12-dependent activation of PI3K requires DAP10 and is inhibited by SHIP1
Peng, Q., Malhotra, S., Torchia, J. A., Kerr, W. G., Coggeshall, K. M., & Humphrey, M. B. (2010) · Science Signaling · doi:10.1126/scisignal.2000500 · Cited by 413 · see citing works
Elevated TREM2 Gene Dosage Reprograms Microglia Responsivity and Ameliorates Pathological Phenotypes in Alzheimer’s Disease Models
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 · see citing works
RIPK1 mediates a disease-associated microglial response in Alzheimer’s disease
Ofengeim, D., Mazzitelli, S., Ito, Y., DeWitt, J. P., Mifflin, L., Zou, C., Das, S., Adiconis, X., Chen, H., Zhu, H., et al. (2017) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1714175114 · Cited by 395 · see citing works
Triggering receptor expressed on myeloid cells 2 (TREM2) deficiency attenuates phagocytic activities of microglia and exacerbates ischemic damage in experimental stroke
Kawabori, M., Kacimi, R., Kauppinen, T., Calosing, C., Kim, J. Y., Hsieh, C. L., Nakamura, M. C., & Yenari, M. A. (2015) · The Journal of Neuroscience · doi:10.1523/jneurosci.2620-14.2015 · Cited by 375 · see citing works
Soluble TREM2 induces inflammatory responses and enhances microglial survival
Zhong, L., Chen, X., Wang, T., Wang, Z., Liao, C., Wang, Z., Huang, R., Wang, D., Li, X., Wu, L., et al. (2017) · The Journal of Experimental Medicine · doi:10.1084/jem.20160844 · Cited by 358 · see citing works
TREM2 deficiency impairs chemotaxis and microglial responses to neuronal injury
Mazaheri, F., Snaidero, N., Kleinberger, G., Madore, C., Daria, A., Werner, G., Krasemann, S., Capell, A., Trümbach, D., Wurst, W., et al. (2017) · The EMBO Reports · doi:10.15252/embr.201743922 · Cited by 351 · see citing works
Distinct and Non-Redundant Roles of Microglia and Myeloid Subsets in Mouse Models of Alzheimer's Disease
Mildner, A., Schlevogt, B., Kierdorf, K., Böttcher, C., Erny, D., Kummer, M. P., Quinn, M., Brück, W., Bechmann, I., Heneka, M. T., et al. (2011) · The Journal of Neuroscience · doi:10.1523/jneurosci.6209-10.2011 · Cited by 351 · see citing works
Cerebrospinal fluid soluble TREM2 is higher in Alzheimer disease and associated with mutation status
Piccio, L., Deming, Y., Del-Águila, J. L., Ghezzi, L., Holtzman, D. M., Fagan, A. M., Fenoglio, C., Galimberti, D., Borroni, B., & Cruchaga, C. (2016) · Acta Neuropathologica · doi:10.1007/s00401-016-1533-5 · Cited by 337 · see citing works
Elucidating the Role of TREM2 in Alzheimer’s Disease
Ulrich, J. D., Ulland, T. K., Colonna, M., & Holtzman, D. M. (2017) · Neuron · doi:10.1016/j.neuron.2017.02.042 · Cited by 325 · see citing works
Self-citation
Macrophage colony-stimulating factor induces the proliferation and survival of macrophages via a pathway involving DAP12 and β-catenin
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 · see citing works
Self-citation
Humanized 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 · see citing works
Self-citation
The Triggering Receptor Expressed on Myeloid Cells 2 Binds Apolipoprotein E
Bailey, C. C., DeVaux, L. B., & Farzan, M. (2015) · Journal of Biological Chemistry · doi:10.1074/jbc.m115.677286 · Cited by 303 · see citing works
Increased cerebrospinal fluid soluble TREM2 concentration in Alzheimer’s disease
Heslegrave, A., Heywood, W., Paterson, R., Magdalinou, N., Svensson, J., Johansson, P., Öhrfelt, A., Blennow, K., Hardy, J., Schott, J., et al. (2016) · Molecular Neurodegeneration · doi:10.1186/s13024-016-0071-x · Cited by 303 · see citing works
TREM2 deficiency exacerbates tau pathology through dysregulated kinase signaling in a mouse model of tauopathy
Bemiller, S. M., McCray, T. J., Allan, K., Formica, S. V., Xu, G., Wilson, G., Kokiko-Cochran, O. N., Crish, S. D., Lasagna-Reeves, C. A., Ransohoff, R. M., et al. (2017) · Molecular Neurodegeneration · doi:10.1186/s13024-017-0216-6 · Cited by 299 · see citing works
Alzheimer's disease‐associated TREM2 variants exhibit either decreased or increased ligand‐dependent activation
Song, W., Hooli, B., Mullin, K., Jin, S. C., Cella, M., Ulland, T. K., Wang, Y., Tanzi, R. E., & Colonna, M. (2017) · Alzheimer's & Dementia · doi:10.1016/j.jalz.2016.07.004 · Cited by 297 · see citing works
Self-citation
Sequential Proteolytic Processing of the Triggering Receptor Expressed on Myeloid Cells-2 (TREM2) Protein by Ectodomain Shedding and γ-Secretase-dependent Intramembranous Cleavage
Wunderlich, 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 · see citing works
Pattern Recognition by TREM-2: Binding of Anionic Ligands
Daws, M. R., Sullam, P. M., Niemi, E. C., Chen, T. T., Tchao, N. K., & Seaman, W. E. (2003) · The Journal of Immunology · doi:10.4049/jimmunol.171.2.594 · Cited by 291 · see citing works
Blockade of TREM‐2 exacerbates experimental autoimmune encephalomyelitis
Piccio, L., Buonsanti, C., Mariani, M., Cella, M., Gilfillan, S., Cross, A. H., Colonna, M., & Panina‐Bordignon, P. (2007) · European Journal of Immunology · doi:10.1002/eji.200636837 · Cited by 284 · see citing works
Self-citation
Early changes in CSF sTREM2 in dominantly inherited Alzheimer’s disease occur after amyloid deposition and neuronal injury
Suárez-Calvet, M., Araque Caballero, M. Á., Kleinberger, G., Bateman, R. J., Fagan, A. M., Morris, J. C., Levin, J., Danek, A., Ewers, M., Haass, C., et al. (2016) · Science Translational Medicine · doi:10.1126/scitranslmed.aag1767 · Cited by 272 · see citing works
An Alzheimer‐associated TREM2 variant occurs at the ADAM cleavage site and affects shedding and phagocytic function
Schlepckow, K., Kleinberger, G., Fukumori, A., Feederle, R., Lichtenthaler, S. F., Steiner, H., & Haass, C. (2017) · EMBO Molecular Medicine · doi:10.15252/emmm.201707672 · Cited by 258 · see citing works
Impaired Differentiation of Osteoclasts in TREM-2–deficient Individuals
Cella, M., Buonsanti, C., Strader, C., Kondo, T., Salmaggi, A., & Colonna, M. (2003) · Journal of Experimental Medicine · doi:10.1084/jem.20022220 · Cited by 256 · see citing works
Self-citation
The genetic causes of basal ganglia calcification, dementia, and bone cysts: DAP12 and TREM2
Klünemann, H. H., Ridha, B. H., Magy, L., Wherrett, J. R., Hemelsoet, D. M., Keen, R. W., De Bleecker, J. L., Rossor, M. N., Marienhagen, J., Klein, H. E., et al. (2005) · Neurology · doi:10.1212/01.wnl.0000160304.00003.ca · Cited by 254 · see citing works
The FTD‐like syndrome causing TREM2 T66M mutation impairs microglia function, brain perfusion, and glucose metabolism
Kleinberger, G., Brendel, M., Mracsko, E. Z., Wefers, B., Groeneweg, L., Xiang, X., Focke, C., Deußing, M., Suárez‐Calvet, M., Mazaheri, F., et al. (2017) · The EMBO Journal · doi:10.15252/embj.201796516 · Cited by 244 · see citing works
Neurodegenerative disease mutations in TREM2 reveal a functional surface and distinct loss-of-function mechanisms
Kober, D. L., Alexander-Brett, J. M., Karch, C. M., Cruchaga, C., Colonna, M., Holtzman, M. J., & Brett, T. J. (2016) · eLife · doi:10.7554/elife.20391 · Cited by 238 · see citing works
Self-citation
Transcriptional profiling of CD11c-positive microglia accumulating around amyloid plaques in a mouse model for Alzheimer’s disease
Kamphuis, W., Kooijman, L., Schetters, S., Orre, M., & Hol, E. M. (2016) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2016.07.007 · Cited by 209 · see citing works
TREM-2 promotes macrophage survival and lung disease after respiratory viral infection
Wu, K., Byers, D. E., Jin, X., Agapov, E., Alexander-Brett, J., Patel, A. C., Cella, M., Gilfilan, S., Colonna, M., Kober, D. L., et al. (2015) · Journal of Experimental Medicine · doi:10.1084/jem.20141732 · Cited by 207 · see citing works
Self-citation
TREM2 shedding by cleavage at the H157‐S158 bond is accelerated for the Alzheimer's disease‐associated H157Y variant
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 · see citing works
SORL1 Is Genetically Associated with Late-Onset Alzheimer’s Disease in Japanese, Koreans and Caucasians
Miyashita, A., Koike, A., Jun, G., Wang, L.-S., Takahashi, S., Matsubara, E., Kawarabayashi, T., Shoji, M., Tomita, N., Arai, H., et al. (2013) · PLoS ONE · doi:10.1371/journal.pone.0058618 · Cited by 196 · see citing works
Development and homeostasis of “resident” myeloid cells: the case of the microglia
Gomez Perdiguero, E., Schulz, C., & Geissmann, F. (2013) · Glia · doi:10.1002/glia.22393 · Cited by 182 · see citing works
Microglia Activation and Anti-inflammatory Regulation in Alzheimer’s Disease
Lue, L., Kuo, Y., Beach, T. G., & Walker, D. G. (2010) · Molecular Neurobiology · doi:10.1007/s12035-010-8106-8 · Cited by 175 · see citing works
Specific lipid recognition is a general feature of CD300 and TREM molecules
Cannon, J. P., O’Driscoll, M., & Litman, G. (2011) · Immunogenetics · doi:10.1007/s00251-011-0562-4 · Cited by 174 · see citing works
Heterozygous TREM2 mutations in frontotemporal dementia
Borroni, B., Ferrari, F., Galimberti, D., Nacmias, B., Barone, C., Bagnoli, S., Fenoglio, C., Piaceri, I., Archetti, S., Bonvicini, C., et al. (2014) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2013.09.017 · Cited by 173 · see citing works
ADAM17 is the main sheddase for the generation of human triggering receptor expressed in myeloid cells (hTREM2) ectodomain and cleaves TREM2 after Histidine 157
Feuerbach, D., Schindler, P. A., Barske, C., Joller, S., Beng-Louka, E., Worringer, K. A., Kommineni, S., Kaykas, A., Ho, D. J., Ye, C., et al. (2017) · Neuroscience Letters · doi:10.1016/j.neulet.2017.09.034 · Cited by 172 · see citing works
TREM2 is associated with the risk of Alzheimer's disease in Spanish population
Benitez, B. A., Cooper, B., Pastor, P., Jin, S.-C., Lorenzo, E., Cervantes, S., & Cruchaga, C. (2013) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2012.12.018 · Cited by 163 · see citing works
Neuropsychiatric and genetic aspects of a new hereditary disease characterized by progressive dementia and lipomembranous polycystic osteodysplasia.
Hakola, H. P. (1972) · PubMed · Cited by 159 · see citing works
A novel compound heterozygous mutation in TREM2 found in a Turkish frontotemporal dementia-like family
Guerreiro, R., Bilgic, B., Guven, G., Brás, J., Rohrer, J., Lohmann, E., Hanagasi, H., Gurvit, H., & Emre, M. (2013) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2013.06.005 · Cited by 158 · see citing works
TREM2 is associated with increased risk for Alzheimer’s disease in African Americans
Jin, S. C., Carrasquillo, M. M., Benitez, B. A., Skorupa, T., Carrell, D., Patel, D., Lincoln, S., Krishnan, S., Kachadoorian, M., Reitz, C., et al. (2015) · Molecular Neurodegeneration · doi:10.1186/s13024-015-0016-9 · Cited by 153 · see citing works
High‐affinity interactions and signal transduction between Aβ oligomers and TREM2
Lessard, C. B., Malnik, S. L., Zhou, Y., Ladd, T. B., Cruz, P. E., Ran, Y., Chakrabaty, P., Mahan, T. E., Holtzman, D. M., Ulrich, J. D., et al. (2018) · EMBO Molecular Medicine · doi:10.15252/emmm.201809027 · Cited by 151 · see citing works
Self-citation
Molecular basis for the loss-of-function effects of the Alzheimer’s disease-associated R47H variant of the immune receptor TREM2
Sudom, A., Talreja, S., Danao, J., Bragg, E., Kegel, R., Min, X., Richardson, J., Zhang, Z., Sharkov, N., Marcora, E., et al. (2018) · Journal of Biological Chemistry · doi:10.1074/jbc.ra118.002352 · Cited by 149 · see citing works
Regulation of microglia development and homeostasis.
Greter, M., & Merad, M. (2013) · Glia · doi:10.1002/glia.22408 · Cited by 141 · see citing works
Cerebrospinal fluid soluble TREM2 in aging and Alzheimer’s disease
Henjum, K., Almdahl, I. S., Årskog, V., Minthon, L., Hansson, O., Fladby, T., & Nilsson, L. N. G. (2016) · Alzheimer s Research & Therapy · doi:10.1186/s13195-016-0182-1 · Cited by 141 · see citing works
DAP12 stabilizes the C-terminal fragment of the triggering receptor expressed on myeloid cells-2 (TREM2) and protects against LPS-induced pro-inflammatory response
Zhong, L., Chen, X.-F., Zhang, Z.-L., Wang, Z., Shi, X.-Z., Xu, K., Zhang, Y.-W., Xu, H., & Bu, G. (2015) · Journal of Biological Chemistry · doi:10.1074/jbc.m115.645986 · Cited by 133 · see citing works
DAP12 Couples c-Fms Activation to the Osteoclast Cytoskeleton by Recruitment of Syk
Zou, W., Reeve, J., Liu, Y., Teitelbaum, S. L., & Ross, F. P. (2008) · Molecular Cell · doi:10.1016/j.molcel.2008.06.023 · Cited by 130 · see citing works
R47H TREM2 variant increases risk of typical early‐onset Alzheimer's disease but not of prion or frontotemporal dementia
Slattery, C. F., Beck, J. A., Harper, L., Adamson, G., Abdi, Z., Uphill, J., Campbell, T., Druyeh, R., Mahoney, C. J., Rohrer, J. D., et al. (2014) · Alzheimer's & Dementia · doi:10.1016/j.jalz.2014.05.1751 · Cited by 119 · see citing works
Assessing the role of the TREM2 p.R47H variant as a risk factor for Alzheimer's disease and frontotemporal dementia
Ruiz, A., Dols-Icardo, O., Bullido, M. J., Pastor, P., Rodríguez-Rodríguez, E., López de Munain, A., de Pancorbo, M. M., Pérez-Tur, J., Álvarez, V., Antonell, A., et al. (2014) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2013.08.011 · Cited by 118 · see citing works
A rare coding variant in TREM2 increases risk for Alzheimer's disease in Han Chinese
Jiang, T., Tan, L., Chen, Q., Tan, M.-S., Zhou, J.-S., Zhu, X.-C., Lu, H., Wang, H.-F., Zhang, Y.-D., & Yu, J.-T. (2016) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2016.02.023 · Cited by 110 · see citing works
Soluble TREM-2 in cerebrospinal fluid from patients with multiple sclerosis treated with natalizumab or mitoxantrone
Öhrfelt, A., Axelsson, M., Malmeström, C., Novakova, L., Heslegrave, A., Blennow, K., Lycke, J., & Zetterberg, H. (2016) · Multiple Sclerosis Journal · doi:10.1177/1352458515624558 · Cited by 99 · see citing works
The Alzheimer’s disease risk factors apolipoprotein E and TREM2 are linked in a receptor signaling pathway
Jendresen, C., Årskog, V., Daws, M. R., & Nilsson, L. N. G. (2017) · Journal of Neuroinflammation · doi:10.1186/s12974-017-0835-4 · Cited by 94 · see citing works
Defining the Microglia Response during the Time Course of Chronic Neurodegeneration
Vincenti, J. E., Murphy, L., Grabert, K., McColl, B. W., Cancellotti, E., Freeman, T. C., & Manson, J. C. (2016) · Journal of Virology · doi:10.1128/jvi.02613-15 · Cited by 88 · see citing works
A data-driven approach links microglia to pathology and prognosis in amyotrophic lateral sclerosis
Cooper-Knock, J., Green, C., Altschuler, G., Wei, W., Bury, J. J., Heath, P. R., Wyles, M., Gelsthorpe, C., Highley, J. R., Lorente-Pons, A., et al. (2017) · Acta Neuropathologica Communications · doi:10.1186/s40478-017-0424-x · Cited by 80 · see citing works
The TREM2-DAP12 signaling pathway in Nasu&ndash;Hakola disease: a molecular genetics perspective
Humphrey, M. B., Xing, J., & Titus, A. (2015) · Research and Reports in Biochemistry · doi:10.2147/rrbc.s58057 · Cited by 77 · see citing works
Modulation of γ- and β-secretases as early prevention against Alzheimer's disease
Voytyuk, I., De Strooper, B., & Chávez-Gutiérrez, L. (2018) · Biological Psychiatry · doi:10.1016/j.biopsych.2017.08.001 · Cited by 67 · see citing works
hnRNPA2B1 and hnRNPA1 mutations are rare in patients with “multisystem proteinopathy” and frontotemporal lobar degeneration phenotypes
Ber, I. L., van Bortel, I., Nicolas, G., Bouya-Ahmed, K., Camuzat, A., Wallon, D., de Septenville, A. L., Latouche, M., Lattante, S., Kabashi, E., et al. (2013) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2013.09.016 · Cited by 65 · see citing works
Rare TREM2 variants associated with Alzheimer’s disease display reduced cell surface expression
Sirkis, D. W., Bonham, L. W., Aparicio, R. E., Geier, E. G., Ramos, E. M., Wang, Q., Karydas, A., Miller, Z. A., Miller, B. L., Coppola, G., et al. (2016) · Acta Neuropathologica Communications · doi:10.1186/s40478-016-0367-7 · Cited by 61 · see citing works
A candidate regulatory variant at the TREM gene cluster associates with decreased Alzheimer's disease risk and increased TREML1 and TREM2 brain gene expression
Carrasquillo, M. M., Allen, M., Burgess, J. D., Wang, X., Strickland, S. L., Aryal, S., Siuda, J., Kachadoorian, M. L., Medway, C., Younkin, C. S., et al. (2017) · Alzheimer's & Dementia · doi:10.1016/j.jalz.2016.10.005 · Cited by 58 · see citing works
Distribution of Misfolded Prion Protein Seeding Activity Alone Does Not Predict Regions of Neurodegeneration
Alibhai, J. D., Blanco, R. A., Barria, M. A., Piccardo, P., Caughey, B. W., Perry, V. H., Freeman, T. C., & Manson, J. C. (2016) · PLoS Biology · doi:10.1371/journal.pbio.1002579 · Cited by 56 · see citing works
Progesterone exerts neuroprotective effects and improves long-term neurologic outcome after intracerebral hemorrhage in middle-aged mice
Jiang, C. Q., Zuo, F., Wang, Y., Wan, J., Yang, Z.-J., Lu, H., Chen, W., Zang, W., Yang, Q., & Wang, J. (2016) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2016.02.029 · Cited by 54 · see citing works
Functional involvement of γ-secretase in signaling of the triggering receptor expressed on myeloid cells-2 (TREM2)
Glebov, K., Wunderlich, P., Karaca, I., & Walter, J. (2016) · Journal of Neuroinflammation · doi:10.1186/s12974-016-0479-9 · Cited by 44 · see citing works
Histologische und histopathologische Arbeiten über die Grosshirnrinde : mit besonderer Berücksichtigung der pathologischen Anatomie der Geisteskrankheiten
Nissl, F., & Alzheimer, A. (1904) · G. Fischer eBooks · Cited by 38 · see citing works
Lack of Genetic Association Between TREM2 and Alzheimer’s Disease in East Asian Population: A Systematic Review and Meta-Analysis
Huang, M., Wang, D., Xu, Z., Xu, Y., Xu, X., Ma, Y., & Xia, Z. (2015) · American Journal of Alzheimer's Disease & Other Dementias® · doi:10.1177/1533317515577128 · Cited by 25 · see citing works
Correction: SORL1 Is Genetically Associated with Late-Onset Alzheimer’s Disease in Japanese, Koreans and Caucasians
Miyashita, A., Koike, A., Jun, G., Wang, L., Takahashi, S., Matsubara, E., Kawarabayashi, T., Shoji, M., Tomita, N., Arai, H., et al. (2013) · PLoS ONE · doi:10.1371/annotation/fcb56ea7-d32a-4e45-818d-39cef330c731 · Cited by 17 · see citing works
A familial frontotemporal dementia associated with C9orf72 repeat expansion and dysplastic gangliocytoma
Ferrari, R., Kero, M., Mok, K. Y., Paetau, A. E., Tienari, P. J., Tynninen, O., Hardy, J., Momeni, P., Verkkoniemi‐Ahola, A., & Myllykangas, L. (2013) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2013.08.021 · Cited by 15 · see citing works
Erratum to “Exploratory analysis of seven Alzheimer's disease genes: disease progression” [Neurobiol. Aging 34 (2013) 1310.e1–1310.e7]
Ruiz, A., Hernández, I., Rosende‐Roca, M., González‐Pérez, A., Rodríguez‐Noriega, E., Ramírez‐Lorca, R., Mauleón, A., Moreno‐Rey, C., Boswell, L., Tune, L. E., et al. (2014) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2014.06.016 · Cited by 5 · see citing works
Emerging Mechanisms in Alzheimer’s Disease and Their Therapeutic Implications
Strittmatter, S. M. (2018) · Biological Psychiatry · doi:10.1016/j.biopsych.2017.12.002 · Cited by 4 · see citing works

Flagged first, then by citations

Sorted by citations

Human and mouse single-nucleus transcriptomics reveal TREM2-dependent and TREM2-independent cellular responses in Alzheimer’s disease
Zhou, 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 · see citing works
Self-citation
Recent advances in Alzheimer's disease: Mechanisms, clinical trials and new drug development strategies.
Zhang, J., Zhang, Y., Wang, J., Xia, Y., Zhang, J., & Chen, L. (2024) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-024-01911-3 · Cited by 1,138 · see citing works
“638,640 – 643 It is worth noting that there remain many uncertainties and controversies regarding the in vivo ligands and signaling pathways of TREM2, as well as the relationship between TREM2 variants and AD.”
Background
TREM2 regulates microglial cholesterol metabolism upon chronic phagocytic challenge
Nugent, A. A., Lin, K., van Lengerich, B., Lianoglou, S., Przybyla, L., Davis, S. S., Llapashtica, C., Wang, J., Kim, D. J., Xia, D., et al. (2020) · Neuron · doi:10.1016/j.neuron.2019.12.007 · Cited by 745 · see citing works
TREM2 Modulation Remodels the Tumor Myeloid Landscape Enhancing Anti-PD-1 Immunotherapy
Molgora, M., Esaulova, E., Vermi, W., Hou, J., Chen, Y., Luo, J., Brioschi, S., Bugatti, M., Omodei, A. S., Ricci, B., et al. (2020) · Cell · doi:10.1016/j.cell.2020.07.013 · Cited by 656 · see citing works
“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).”
Self-citation
Plasma GFAP is an early marker of amyloid-β but not tau pathology in Alzheimer's disease
Pereira, J. B., Janelidze, S., Smith, R., Mattsson-Carlgren, N., Palmqvist, S., Teunissen, C. E., Zetterberg, H., Stomrud, E., Ashton, N. J., Blennow, K., et al. (2021) · Brain · doi:10.1093/brain/awab223 · Cited by 598 · see citing works
The Physiology, Pathology, and Potential Therapeutic Applications of the TREM2 Signaling Pathway
Deczkowska, A., Weiner, A., & Amit, I. (2020) · Cell · doi:10.1016/j.cell.2020.05.003 · Cited by 648 · see citing works
Coupled scRNA-Seq and Intracellular Protein Activity Reveal an Immunosuppressive Role of TREM2 in Cancer
Katzenelenbogen, Y., Sheban, F., Yalin, A., Yofe, I., Svetlichnyy, D., Jaitin, D. A., Bornstein, C., Moshe, A., Keren-Shaul, H., Cohen, M., et al. (2020) · Cell · doi:10.1016/j.cell.2020.06.032 · Cited by 498 · see citing works
Microglia use TAM receptors to detect and engulf amyloid β plaques
Huang, Y., Happonen, K. E., Burrola, P. G., O’Connor, C., Hah, N., Huang, L., Nimmerjahn, A., & Lemke, G. (2021) · Nature Immunology · doi:10.1038/s41590-021-00913-5 · Cited by 483 · see citing works
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 · see citing works
Self-citation
Lipid metabolism and Alzheimer's disease: clinical evidence, mechanistic link and therapeutic promise
Yin, F. (2023) · The FEBS Journal · doi:10.1111/febs.16344 · Cited by 441 · see citing works
TREM2 activation on microglia promotes myelin debris clearance and remyelination in a model of multiple sclerosis
Cignarella, F., Filipello, F., Bollman, B., Cantoni, C., Locca, A., Mikesell, R., Manis, M., Ibrahim, A., Deng, L., Benitez, B. A., et al. (2020) · Acta Neuropathologica · doi:10.1007/s00401-020-02193-z · Cited by 392 · see citing works
The role of innate immune responses and neuroinflammation in amyloid accumulation and progression of Alzheimer's disease
Webers, A., Heneka, M. T., & Gleeson, P. A. (2019) · Immunology and Cell Biology · doi:10.1111/imcb.12301 · Cited by 371 · see citing works
Immune Signaling in Neurodegeneration
Hammond, T. R., Marsh, S. E., & Stevens, B. (2019) · Immunity · doi:10.1016/j.immuni.2019.03.016 · Cited by 336 · see citing works
Emerging roles of innate and adaptive immunity in Alzheimer’s disease
Chen, X., & Holtzman, D. M. (2022) · Immunity · doi:10.1016/j.immuni.2022.10.016 · Cited by 297 · see citing works
Amyloid β, Tau, and α-Synuclein aggregates in the pathogenesis, prognosis, and therapeutics for neurodegenerative diseases
Sengupta, U., & Kayed, R. (2022) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2022.102270 · Cited by 303 · see citing works
Microglia in depression: current perspectives
Jia, X., Gao, Z., & Hu, H. (2020) · Science China Life Sciences · doi:10.1007/s11427-020-1815-6 · Cited by 283 · see citing works
APOE in the bullseye of neurodegenerative diseases: impact of the APOE genotype in Alzheimer’s disease pathology and brain diseases
Fernández-Calle, R., Konings, S. C., Frontiñán-Rubio, J., García-Revilla, J., Camprubí-Ferrer, L., Svensson, M., Martinson, I., Boza-Serrano, A., Venero, J. L., Nielsen, H. M., et al. (2022) · Molecular Neurodegeneration · doi:10.1186/s13024-022-00566-4 · Cited by 278 · see citing works
Brain borders at the central stage of neuroimmunology
Rustenhoven, J., & Kipnis, J. (2022) · Nature · doi:10.1038/s41586-022-05474-7 · Cited by 253 · see citing works
Alzheimer’s-associated PLCγ2 is a signaling node required for both TREM2 function and the inflammatory response in human microglia
Andreone, B. J., Przybyla, L., Llapashtica, C., Rana, A., Davis, S. S., van Lengerich, B., Lin, K., Shi, J., Mei, Y., Astarita, G., et al. (2020) · Nature Neuroscience · doi:10.1038/s41593-020-0650-6 · Cited by 233 · see citing works
Microglia and Neuroinflammation: Crucial Pathological Mechanisms in Traumatic Brain Injury-Induced Neurodegeneration
Shao, F., Wang, X., Wu, H., Wu, Q., & Zhang, J. (2022) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2022.825086 · Cited by 250 · see citing works
Microglia in Brain Development, Homeostasis, and Neurodegeneration
Bohlen, C. J., Friedman, B. A., Dejanovic, B., & Sheng, M. (2019) · Annual Review of Genetics · doi:10.1146/annurev-genet-112618-043515 · Cited by 212 · see citing works
Microglia-neuron crosstalk: Signaling mechanism and control of synaptic transmission
Marinelli, S., Basilico, B., Marrone, M. C., & Ragozzino, D. (2019) · Seminars in Cell & Developmental Biology · doi:10.1016/j.semcdb.2019.05.017 · Cited by 233 · see citing works
A TREM2-activating antibody with a blood–brain barrier transport vehicle enhances microglial metabolism in Alzheimer’s disease models
van Lengerich, B., Zhan, L., Xia, D., Chan, D., Joy, D., Park, J. I., Tatarakis, D., Calvert, M., Hummel, S., Lianoglou, S., et al. (2023) · Nature Neuroscience · doi:10.1038/s41593-022-01240-0 · Cited by 233 · see citing works
Microglia reprogram metabolic profiles for phenotype and function changes in central nervous system
Yang, S., Qin, C., Hu, Z.-W., Zhou, L.-Q., Yu, H.-H., Chen, M., Bosco, D. B., Wang, W., Wu, L.-J., & Tian, D.-S. (2021) · Neurobiology of Disease · doi:10.1016/j.nbd.2021.105290 · Cited by 232 · see citing works
Alzheimer’s Risk Factors Age, APOE Genotype, and Sex Drive Distinct Molecular Pathways
Zhao, N., Ren, Y., Yamazaki, Y., Qiao, W., Li, F., Felton, L. M., Mahmoudiandehkordi, S., Kueider-Paisley, A., Sonoustoun, B., Arnold, M., et al. (2020) · Neuron · doi:10.1016/j.neuron.2020.02.034 · Cited by 225 · see citing works
TREM2hi resident macrophages protect the septic heart by maintaining cardiomyocyte homeostasis
Zhang, K., Wang, Y., Chen, S., Mao, J., Jin, Y., Ye, H., Zhang, Y., Liu, X., Gong, C., Cheng, X., et al. (2023) · Nature Metabolism · doi:10.1038/s42255-022-00715-5 · Cited by 216 · see citing works
Mouse Models of Alzheimer’s Disease
Yokoyama, M., Kobayashi, H., Tatsumi, L., & Tomita, T. (2022) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2022.912995 · Cited by 213 · see citing works
Trem2 Deletion Reduces Late-Stage Amyloid Plaque Accumulation, Elevates the Aβ42:Aβ40 Ratio, and Exacerbates Axonal Dystrophy and Dendritic Spine Loss in the PS2APP Alzheimer's Mouse Model
Meilandt, W. J., Ngu, H., Gogineni, A., Lalehzadeh, G., Lee, S.-H., Srinivasan, K., Imperio, J., Wu, T., Weber, M., Kruse, A. J., et al. (2020) · The Journal of Neuroscience · doi:10.1523/jneurosci.1871-19.2019 · Cited by 210 · see citing works
“…compaction of A into dense plaques is a protective microglial activity, limiting the exposure of neurons to toxic A species. tive or detrimental functions in mouse models of AD-related neuropathology has been rather unclear (Gratuze et al., 2018; Hansen et al., 2018; Ulland and Colonna, 2018).”
Background
Targeting neuroinflammation in Alzheimer’s disease: from mechanisms to clinical applications
Si, Z.-Z., Zou, C.-J., Mei, X., Mei, X., Luo, H., Shen, Y., Hu, J., Li, X.-X., Wu, L., & Liu, Y. (2022) · Neural Regeneration Research · doi:10.4103/1673-5374.353484 · Cited by 192 · see citing works
Trem2 promotes foamy macrophage lipid uptake and survival in atherosclerosis
Patterson, M. T., Firulyova, M. M., Xu, Y., Hillman, H., Bishop, C., Zhu, A., Hickok, G. H., Schrank, P. R., Ronayne, C. E., Caillot, Z., et al. (2023) · Nature Cardiovascular Research · doi:10.1038/s44161-023-00354-3 · Cited by 186 · see citing works
Role of Oxidative Damage in Alzheimer’s Disease and Neurodegeneration: From Pathogenic Mechanisms to Biomarker Discovery
Buccellato, F. R., D’Anca, M., Fenoglio, C., Scarpini, E., & Galimberti, D. (2021) · Antioxidants · doi:10.3390/antiox10091353 · Cited by 179 · see citing works
Directed evolution of adeno-associated virus for efficient gene delivery to microglia
Lin, R., Zhou, Y., Yan, T., Wang, R., Li, H., Wu, Z., Zhang, X., Zhou, X., Zhao, F., Zhang, L., et al. (2022) · Nature Methods · doi:10.1038/s41592-022-01547-7 · Cited by 171 · see citing works
Origins, Biology, and Diseases of Tissue Macrophages
Cox, N., Pokrovskii, M. V., Vicario, R., & Geissmann, F. (2021) · Annual Review of Immunology · doi:10.1146/annurev-immunol-093019-111748 · Cited by 162 · see citing works
Brain cell type-specific cholesterol metabolism and implications for learning and memory
Li, D., Zhang, J., & Liu, Q. (2022) · Trends in Neurosciences · doi:10.1016/j.tins.2022.01.002 · Cited by 163 · see citing works
Neuroimmune Connections in Aging and Neurodegenerative Diseases
Scheiblich, H., Trombly, M., Ramirez, A., & Heneka, M. T. (2020) · Trends in Immunology · doi:10.1016/j.it.2020.02.002 · Cited by 166 · see citing works
Neuroinflammatory Processes, A1 Astrocyte Activation and Protein Aggregation in the Retina of Alzheimer’s Disease Patients, Possible Biomarkers for Early Diagnosis
Grimaldi, A., Pediconi, N., Oieni, F., Pizzarelli, R., Rosito, M., Giubettini, M., Santini, T., Limatola, C., Ruocco, G., Ragozzino, D., et al. (2019) · Frontiers in Neuroscience · doi:10.3389/fnins.2019.00925 · Cited by 153 · see citing works
TREM2 interacts with TDP-43 and mediates microglial neuroprotection against TDP-43-related neurodegeneration
Xie, M., Liu, Y. U., Zhao, S., Zhang, L., Bosco, D. B., Pang, Y.-P., Zhong, J., Sheth, U., Martens, Y. A., Zhao, N., et al. (2022) · Nature Neuroscience · doi:10.1038/s41593-021-00975-6 · Cited by 157 · see citing works
Translating genetic risk of Alzheimer’s disease into mechanistic insight and drug targets
Sierksma, A. S. R., Escott‐Price, V., & Strooper, B. D. (2020) · Science · doi:10.1126/science.abb8575 · Cited by 149 · see citing works
C9orf72 deficiency promotes microglial-mediated synaptic loss in aging and amyloid accumulation
Lall, D., Lorenzini, I., Mota, T. A., Bell, S., Mahan, T. E., Ulrich, J. D., Davtyan, H., Rexach, J. E., Muhammad, A. K. M. G., Shelest, O., et al. (2021) · Neuron · doi:10.1016/j.neuron.2021.05.020 · Cited by 147 · see citing works
A tetravalent TREM2 agonistic antibody reduced amyloid pathology in a mouse model of Alzheimer’s disease
Zhao, P., Xu, Y., Jiang, L., Fan, X., Li, L., Li, X., Arase, H., Zhao, Y., Cao, W., Zheng, H., et al. (2022) · Science Translational Medicine · doi:10.1126/scitranslmed.abq0095 · Cited by 141 · see citing works
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. B., Case, R. B., Yoo, D., Weishuhn, D., Rathanaswami, P., Bradley, J., et al. (2021) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2017742118 · Cited by 143 · see citing works
Self-citation
Alzheimer’s disease phospholipase C-gamma-2 (PLCG2) protective variant is a functional hypermorph
Magno, L., Lessard, C. B., Martins, M., Lang, V., Cruz, P., Asi, Y., Katan, M., Bilsland, J., Lashley, T., Chakrabarty, P., et al. (2019) · Alzheimer's Research & Therapy · doi:10.1186/s13195-019-0469-0 · Cited by 143 · see citing works
Protective Microglial Subset in Development, Aging, and Disease: Lessons From Transcriptomic Studies
Benmamar‐Badel, A., Owens, T., & Włodarczyk, A. (2020) · Frontiers in Immunology · doi:10.3389/fimmu.2020.00430 · Cited by 135 · see citing works
New Insights Into Drug Discovery Targeting Tau Protein
Soeda, Y., & Takashima, A. (2020) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2020.590896 · Cited by 133 · see citing works
Microglial mTOR Activation Upregulates Trem2 and Enhances β-Amyloid Plaque Clearance in the 5XFAD Alzheimer's Disease Model
Shi, Q., Chang, C., Saliba, A., & Bhat, M. A. (2022) · Journal of Neuroscience · doi:10.1523/jneurosci.2427-21.2022 · Cited by 133 · see citing works
Transgenic Mouse Models of Alzheimer’s Disease: An Integrative Analysis
Sanchez-Varo, R. M., Mejias‐Ortega, M., Fernandez-Valenzuela, J. J., Nuñez‐Diaz, C., Cáceres-Palomo, L., Vegas‐Gomez, L., Sánchez‐Mejías, E., Trujillo‐Estrada, L., García‐León, J. A., Moreno‐González, I., et al. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23105404 · Cited by 130 · see citing works
Preclinical Models of Alzheimer's Disease: Relevance and Translational Validity
Mullane, K., & Williams, M. (2019) · Current Protocols in Pharmacology · doi:10.1002/cpph.57 · Cited by 122 · see citing works
TREM2: Potential therapeutic targeting of microglia for Alzheimer's disease
Li, Y., Xu, H., Wang, H., Yang, K., Luan, J., & Wang, S. (2023) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2023.115218 · Cited by 128 · see citing works
Microglia in Alzheimer’s Disease in the Context of Tau Pathology
Perea, J. R., Bolós, M., & Ávila, J. (2020) · Biomolecules · doi:10.3390/biom10101439 · Cited by 127 · see citing works
Alzheimer’s Disease: Novel Targets and Investigational Drugs for Disease Modification
Cummings, J. L., Osse, A. M. L., & Kinney, J. W. (2023) · Drugs · doi:10.1007/s40265-023-01938-w · Cited by 123 · see citing works
TREM2 regulates microglial lipid droplet formation and represses post-ischemic brain injury
Wei, W., Zhang, L., Xin, W., Pan, Y., Tatenhorst, L., Hao, Z., Gerner, S. T., Huber, S., Juenemann, M., Butz, M., et al. (2024) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2023.115962 · Cited by 122 · see citing works
Disease-Modifying Therapies for Alzheimer’s Disease: More Questions than Answers
Golde, T. E. (2022) · Neurotherapeutics · doi:10.1007/s13311-022-01201-2 · Cited by 119 · see citing works
pHERV-W envelope protein fuels microglial cell-dependent damage of myelinated axons in multiple sclerosis
Kremer, D., Gruchot, J., Weyers, V., Oldemeier, L., Göttle, P., Healy, L. M., Jang, J. H., Xu, Y. K. T., Volsko, C. M., Dutta, R., et al. (2019) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1901283116 · Cited by 119 · see citing works
Leveraging preclinical models for the development of Alzheimer disease therapeutics
Scearce-Levie, K. A., Sanchez, P. E., & Lewcock, J. W. (2020) · Nature Reviews Drug Discovery · doi:10.1038/s41573-020-0065-9 · Cited by 118 · see citing works
The role of innate immunity in Alzheimer's disease
Ennerfelt, H. E., & Lukens, J. R. (2020) · Immunological Reviews · doi:10.1111/imr.12896 · Cited by 121 · see citing works
Decoding microglial immunometabolism: a new frontier in Alzheimer's disease research
Jung, E. S., Choi, H., & Mook-Jung, I. (2025) · Molecular Neurodegeneration · doi:10.1186/s13024-025-00825-0 · Cited by 124 · see citing works
Pharmacokinetics and pharmacodynamics of a single dose Nilotinib in individuals with Parkinson's disease
Pagán, F., Hebron, M. L., Wilmarth, B., Torres-Yaghi, Y. A., Lawler, A., Mundel, E. E., Yusuf, N., Starr, N. J., Arellano, J., Howard, H. H., et al. (2019) · Pharmacology Research & Perspectives · doi:10.1002/prp2.470 · Cited by 117 · see citing works
Stimulation of TREM2 with agonistic antibodies—an emerging therapeutic option for Alzheimer's disease
Schlepckow, K., Morenas‐Rodríguez, E., Hong, S. Y., & Haass, C. (2023) · The Lancet Neurology · doi:10.1016/s1474-4422(23)00247-8 · Cited by 121 · see citing works
Neuropathogenesis-on-chips for neurodegenerative diseases
Amartumur, S., Nguyen, H. M., Huynh, T., Kim, T. S., Woo, R., Oh, E., Kim, K. K., Lee, L. P., & Heo, C. (2024) · Nature Communications · doi:10.1038/s41467-024-46554-8 · Cited by 120 · see citing works
Single-nucleus transcriptomic landscape of primate hippocampal aging
Zhang, H., Li, J., Ren, J., Sun, S., Ma, S., Zhang, W., Yu, Y., Cai, Y., Yan, K., Li, W., et al. (2021) · Protein & Cell · doi:10.1007/s13238-021-00852-9 · Cited by 118 · see citing works
Phosphorylation Signaling in APP Processing in Alzheimer’s Disease
Zhang, T., Chen, D., & Lee, T. H. (2019) · International Journal of Molecular Sciences · doi:10.3390/ijms21010209 · Cited by 114 · see citing works
Trem2 mediated Syk-dependent ROS amplification is essential for osteoclastogenesis in periodontitis microenvironment
Weng, Y., Wang, H., Li, L., Feng, Y., Xu, S., & Wang, Z. (2020) · Redox Biology · doi:10.1016/j.redox.2020.101849 · Cited by 114 · see citing works
Control of immune cell function by the unfolded protein response
Conza, G. D., Ho, P., Cubillos‐Ruiz, J. R., & Huang, S. C. (2023) · Nature reviews. Immunology · doi:10.1038/s41577-023-00838-0 · Cited by 112 · see citing works
Intranasal Administration of miR-146a Agomir Rescued the Pathological Process and Cognitive Impairment in an AD Mouse Model
Mai, H.-F., Fan, W., Wang, Y., Cai, Y.-J., Li, X., Chen, F., Chen, X., Yang, J.-Q., Tang, P., Chen, H.-Y., et al. (2019) · Molecular Therapy: Nucleic Acids · doi:10.1016/j.omtn.2019.10.002 · Cited by 101 · see citing works
Engagement of TREM2 by a novel monoclonal antibody induces activation of microglia and improves cognitive function in Alzheimer’s disease models
Fassler, M., Rappaport, M., Benaim, C., & George, J. (2021) · Journal of Neuroinflammation · doi:10.1186/s12974-020-01980-5 · Cited by 110 · see citing works
Using a pan-cancer atlas to investigate tumour associated macrophages as regulators of immunotherapy response
Coulton, A., Murai, J., Qian, D., Thakkar, K., Lewis, C. E., & Litchfield, K. (2024) · Nature Communications · doi:10.1038/s41467-024-49885-8 · Cited by 114 · see citing works
A novel tau‐based rhesus monkey model of Alzheimer's pathogenesis
Beckman, D., Chakrabarty, P., Ott, S. P., Dao, A., Zhou, E., Janssen, W. G. M., Donis‐Cox, K., Muller, S., Kordower, J. H., & Morrison, J. H. (2021) · Alzheimer s & Dementia · doi:10.1002/alz.12318 · Cited by 112 · see citing works
Microglial Metabolic Reprogramming: Emerging Insights and Therapeutic Strategies in Neurodegenerative Diseases
Miao, J., Chen, L., Pan, X., Li, L.-Q., Zhao, B., & Lan, J. X. (2023) · Cellular and Molecular Neurobiology · doi:10.1007/s10571-023-01376-y · Cited by 110 · see citing works
Microglia in Alzheimer’s disease: A target for immunotherapy
Wang, S., & Colonna, M. (2019) · Journal of Leukocyte Biology · doi:10.1002/jlb.mr0818-319r · Cited by 104 · see citing works
Self-citation
Prebiotics Regulation of Intestinal Microbiota Attenuates Cognitive Dysfunction Induced by Surgery Stimulation in APP/PS1 Mice
Han, D., Li, Z., Liu, T., Yang, N., Li, Y., He, J., Qian, M., Kuang, Z., Zhang, W., Ni, C., et al. (2020) · Aging and Disease · doi:10.14336/ad.2020.0106 · Cited by 99 · see citing works
TREM2 in Alzheimer’s Disease: Microglial Survival and Energy Metabolism
Zheng, H., Cheng, B., Li, Y., Li, X., Chen, X., & Zhang, Y.-W. (2018) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2018.00395 · Cited by 94 · see citing works
Integrated Analysis Highlights the Immunosuppressive Role of TREM2+ Macrophages in Hepatocellular Carcinoma
Zhou, L., Wang, M., Guo, H., Hou, J., Zhang, Y., Li, M., Wu, X., Chen, X., & Wang, L. (2022) · Frontiers in Immunology · doi:10.3389/fimmu.2022.848367 · Cited by 85 · see citing works
Maternal immune activation induces autism-like changes in behavior, neuroinflammatory profile and gut microbiota in mouse offspring of both sexes
Tartaglione, A. M., Villani, A., Ajmone‐Cat, M. A., Minghetti, L., Ricceri, L., Pazienza, V., Simone, R. D., & Calamandrei, G. (2022) · Translational Psychiatry · doi:10.1038/s41398-022-02149-9 · Cited by 94 · see citing works
<scp>TREM2</scp>‐induced activation of microglia contributes to synaptic integrity in cognitively intact aged individuals with Alzheimer's neuropathology
Fracassi, A., Marcatti, M., Tumurbaatar, B., Woltjer, R., Moreno, S., & Taglialatela, G. (2023) · Brain Pathology · doi:10.1111/bpa.13108 · Cited by 92 · see citing works
Platinum‐Based TREM2 Inhibitor Suppresses Tumors by Remodeling the Immunosuppressive Microenvironment
Yang, T., Zhang, S., Yuan, H., Wang, Y., Cai, L., Chen, H., Wang, X., Song, D., Wang, X., Guo, Z., et al. (2022) · Angewandte Chemie International Edition · doi:10.1002/anie.202213337 · Cited by 90 · see citing works
Noteworthy perspectives on microglia in neuropsychiatric disorders
Zhu, H., Guan, A., Liu, J., Li, P., Zhang, Z., & Wang, S. (2023) · Journal of Neuroinflammation · doi:10.1186/s12974-023-02901-y · Cited by 90 · see citing works
Pathological mechanisms and treatment progression of Alzheimer’s disease
Zhang, J., Kong, G., Yang, J., Pang, L., & Li, X. (2025) · European journal of medical research · doi:10.1186/s40001-025-02886-9 · Cited by 94 · see citing works
Carbonic Anhydrases as Potential Targets Against Neurovascular Unit Dysfunction in Alzheimer’s Disease and Stroke
Lemon, N. L., Canepa, E., Ilies, M. A., & Fossati, S. (2021) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2021.772278 · Cited by 84 · see citing works
Adult-Onset Leukoencephalopathy With Axonal Spheroids and Pigmented Glia: Review of Clinical Manifestations as Foundations for Therapeutic Development
Papapetropoulos, S., Pontius, A., Finger, E. C., Karrenbauer, V. D., Lynch, D. S., Brennan, M. J., Zappia, S., Koehler, W., Schöls, L. J., Hayer, S. N., et al. (2022) · Frontiers in Neurology · doi:10.3389/fneur.2021.788168 · Cited by 80 · see citing works
Sphingolipids in neuroinflammation: a potential target for diagnosis and therapy
Lee, J. Y., Jin, H. K., & Bae, J.-S. (2020) · BMB Reports · doi:10.5483/bmbrep.2020.53.1.278 · Cited by 80 · see citing works
Functional insights from biophysical study of TREM2 interactions with apoE and Aβ 1‐42
Kober, D. L., Stuchell‐Brereton, M. D., Kluender, C. E., Dean, H. B., Strickland, M. R., Steinberg, D. F., Nelson, S. S., Baban, B. A., Holtzman, D. M., Frieden, C., et al. (2020) · Alzheimer s & Dementia · doi:10.1002/alz.12194 · Cited by 81 · see citing works
Peripheral and central neuroimmune mechanisms in Alzheimer’s disease pathogenesis
Zhang, S., Gao, Y., Zhao, Y., Huang, T. Y., Zheng, Q., & Wang, X. (2025) · Molecular Neurodegeneration · doi:10.1186/s13024-025-00812-5 · Cited by 78 · see citing works
Biomarkers and therapeutic strategies targeting microglia in neurodegenerative diseases: current status and future directions
Noh, M., Kwon, H. S., Kwon, M., Nahm, M., Jin, H. K., Bae, J., & Kim, S. H. (2025) · Molecular Neurodegeneration · doi:10.1186/s13024-025-00867-4 · Cited by 84 · see citing works
What are activated and reactive glia and what is their role in neurodegeneration?
Bennett, M. L., & Viaene, A. N. (2021) · Neurobiology of Disease · doi:10.1016/j.nbd.2020.105172 · Cited by 77 · see citing works
Diversity and Function of Glial Cell Types in Multiple Sclerosis
Schirmer, L., Schafer, D. P., Bartels, T., Rowitch, D. H., & Calabresi, P. A. (2021) · Trends in Immunology · doi:10.1016/j.it.2021.01.005 · Cited by 75 · see citing works
APOE4 confers transcriptomic and functional alterations to primary mouse microglia
Machlovi, S. I., Neuner, S. M., Hemmer, B. M., Khan, R., Liu, Y., Huang, M., Zhu, J. D., Castellano, J. M., Cai, D., Marcora, E., et al. (2022) · Neurobiology of Disease · doi:10.1016/j.nbd.2022.105615 · Cited by 73 · see citing works
Remembering your A, B, C's: Alzheimer's disease and ABCA1
Lewandowski, C. T., Laham, M. S., & Thatcher, G. R. J. (2022) · Acta Pharmaceutica Sinica B · doi:10.1016/j.apsb.2022.01.011 · Cited by 76 · see citing works
TREM2: A new player in the tumor microenvironment
Molgora, M., Liu, Y. A., Colonna, M., & Cella, M. (2023) · Seminars in Immunology · doi:10.1016/j.smim.2023.101739 · Cited by 76 · see citing works
Self-citation
Hepatic danger signaling triggers TREM2 + macrophage induction and drives steatohepatitis via MS4A7-dependent inflammasome activation
Zhou, L., Qiu, X., Meng, Z., Liu, T., Chen, Z., Zhang, P., Kuang, H., Pan, T., Lu, Y., Qi, L., et al. (2024) · Science Translational Medicine · doi:10.1126/scitranslmed.adk1866 · Cited by 81 · see citing works
Loss of TREM2 Confers Resilience to Synaptic and Cognitive Impairment in Aged Mice
Qu, W., & Li, L. (2020) · Journal of Neuroscience · doi:10.1523/jneurosci.2193-20.2020 · Cited by 70 · see citing works
TREM2 promotes lung fibrosis via controlling alveolar macrophage survival and pro-fibrotic activity
Cui, H., Banerjee, S., Xie, N., Hussain, M., Jaiswal, A., Liu, H., Kulkarni, T., Antony, V. B., Liu, R.-M., Colonna, M., et al. (2025) · Nature Communications · doi:10.1038/s41467-025-57024-0 · Cited by 74 · see citing works
“This receptor consists of an extracellular V-type Ig domain followed by a short stalk and a single transmembrane helix that interacts with the immunoreceptor tyrosine-based activation motif (ITAM) containing DNAX-activation protein 12 (DAP12) 29,30 .”
InfluentialSelf-citation
CD33 isoforms in microglia and Alzheimer's disease: Friend and foe
Eskandari‐Sedighi, G., Jung, J., & Macauley, M. S. (2022) · Molecular Aspects of Medicine · doi:10.1016/j.mam.2022.101111 · Cited by 68 · see citing works
Brain Parenchymal and Extraparenchymal Macrophages in Development, Homeostasis, and Disease
Brioschi, S., Zhou, Y., & Colonna, M. (2020) · The Journal of Immunology · doi:10.4049/jimmunol.1900821 · Cited by 65 · see citing works
Self-citation
Soluble TREM2 inhibits secondary nucleation of Aβ fibrillization and enhances cellular uptake of fibrillar Aβ
Belsare, K. D., Wu, H., Mondal, D., Bond, A., Castillo, E., Jin, J., Jo, H., Roush, A. E., Pilla, K. B., Sali, A., et al. (2022) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2114486119 · Cited by 68 · see citing works
Reducing microglial lipid load enhances β amyloid phagocytosis in an Alzheimer’s disease mouse model
Wu, X., Miller, J. A., Lee, B. T. K., Wang, Y., & Ruedl, C. (2025) · Science Advances · doi:10.1126/sciadv.adq6038 · Cited by 67 · see citing works
“Mutations affecting the TREM2 function impair microglial activation ( 37 ) and reduce their ability to accumulate LDs in the AD brain ( 38 ).”
Metabolic Regulation of Glia and Their Neuroinflammatory Role in Alzheimer's Disease
Kumari, P., Sood, A., & Fernandes, V. (2021) · Cellular and Molecular Neurobiology · doi:10.1007/s10571-021-01147-7 · Cited by 67 · see citing works
TREM2/PLCγ2 signalling in immune cells: function, structural insight, and potential therapeutic modulation
Magno, L., Bunney, T. D., Mead, E., Svensson, F., & Bictash, M. N. (2021) · Molecular Neurodegeneration · doi:10.1186/s13024-021-00436-5 · Cited by 64 · see citing works
Microglia gone awry: linking immunometabolism to neurodegeneration
Afridi, R., Lee, W.-H., & Suk, K. (2020) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2020.00246 · Cited by 64 · see citing works
Psychedelic‐inspired approaches for treating neurodegenerative disorders
Saeger, H. N., & Olson, D. E. (2021) · Journal of Neurochemistry · doi:10.1111/jnc.15544 · Cited by 65 · see citing works
Microglial Function and Regulation during Development, Homeostasis and Alzheimer’s Disease
Casali, B. T., & Reed-Geaghan, E. G. (2021) · Cells · doi:10.3390/cells10040957 · Cited by 64 · see citing works

Authors: Ulland, T. K., & Colonna, M.
Affiliations: University of Wisconsin–Madison (US)
Washington University in St. Louis (US)
Corresponding author: Colonna, Marco
ORCID: Ulland, Tyler K.
Colonna, Marco
Venue: Nature Reviews Neurology
Publisher: Springer Science and Business Media LLC
Published: 2018-09-28
Volume: 14
Issue: 11
Pages: 667-675
ISSN: 1759-4758 (ISSN-L)
1759-4766
DOI: 10.1038/s41582-018-0072-1
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 · 2012: 1
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
Health Sciences › Medicine › Physiology › 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

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

TREM2 — a key player in microglial biology and Alzheimer disease

Abstract

Integrity signals

Claims the paper makes

Claims other papers make about this one

Cites

Cited by

Related

Record

About these checks