TREM2 Is a Receptor for β-Amyloid that Mediates Microglial Function
Open accessAbstract
Mutations in triggering receptor expressed on myeloid cells 2 (TREM2) have been linked to increased Alzheimer's disease (AD) risk. Neurobiological functions of TREM2 and its pathophysiological ligands remain elusive. Here we found that TREM2 directly binds to β-amyloid (Aβ) oligomers with nanomolar affinity, whereas AD-associated TREM2 mutations reduce Aβ binding. TREM2 deficiency impairs Aβ degradation in primary microglial culture and mouse brain. Aβ-induced microglial depolarization, K+ inward current induction, cytokine expression and secretion, migration, proliferation, apoptosis, and morphological changes are dependent on TREM2. In addition, TREM2 interaction with its signaling adaptor DAP12 is enhanced by Aβ, regulating downstream phosphorylation of SYK and GSK3β. Our data demonstrate TREM2 as a microglial Aβ receptor transducing physiological and AD-related pathological effects associated with Aβ.
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TREM2 activation supports microglia's migration toward amyloid plaques, preventing amyloid spread.
“Ordinarily, TREM2 activation is considered as a beneficial response in that it supports microglia’s migration toward amyloid plaques, preventing amyloid spread221–224”
From Role of neuroinflammation in neurodegeneration development (2023) · cites this paper as [221]
The Results section on TREM2 deficiency in vivo says TREM2 drives microglial migration to sites of Aβ enrichment and mediates Aβ clearance. It does not establish that this migration prevents amyloid spread; the Discussion says TREM2’s effects on plaque deposition differ across models and that a definitive mechanism has not been established. No page numbers are available in our copy. (LLM, conf=0.85)
Experimental — accuracy not yet measuredTREM2, expressed by DAM/MGnD, exerts protective function in AD via ligation of ApoE or Aβ oligomers.
“TREM2, a receptor expressed by DAM/MGnD, which exerts its protective function in AD via ligation of ApoE (apolipoprotein E), which binds to loose Aβ aggregates, or direct ligation of Aβ oligomers [286, 295, 338, 357, 366]”
From Microglia and monocytes in inflammatory CNS disease: integrating phenotype and function (2022) · cites this paper as [366]
The Results section, “TREM2 Binds to Aβ Oligomers” (page unavailable), demonstrates direct binding, and the in vivo Results describe TREM2-mediated Aβ degradation and microglial responses. The Discussion identifies ApoE as a TREM2 ligand but says its interplay with Aβ remains to be determined; it also cautions that a definitive model of TREM2’s role in AD has not been established. The cited passages do not establish ApoE binding to loose Aβ aggregates or expression specifically by DAM/MGnD. (LLM, conf=0.88)
Experimental — accuracy not yet measuredSeveral other AD risk polymorphisms, such as the R47H TREM2 mutation, alter microglial phagocytic capacity, leading to reduced clearance of Aβ aggregates and neuronal decline.
“Several other polymorphisms implicated as risk factors in AD, such as the R47H TREM2 mutation, result in alterations to microglial phagocytic capacity that lead to reduced clearance of Aβ aggregates and neuronal decline [27, 28].”
From Heterozygous expression of the Alzheimer’s disease-protective PLCγ2 P522R variant enhances Aβ clearance while preserving synapses (2022) · cites this paper as [28]
The Introduction identifies R47H as an AD-risk variant, and the Results (‘TREM2 Binds to Aβ Oligomers’; page unavailable) show that it compromises TREM2 binding to Aβ oligomers. But the Results on Aβ degradation report that TREM2 deletion had little effect on microglial phagocytic uptake, while reducing degradation after uptake. The paper does not establish that R47H causes reduced clearance of Aβ aggregates or consequent neuronal decline. (LLM, conf=0.90)
Experimental — accuracy not yet measuredTREM2 binding to Aβ promotes its phagocytosis by microglia, which induces secretion of pro-inflammatory cytokines IL-6 and CCL3, increases microglial proliferation, migration, and apoptosis, and reduces intracellular K+ concentrations.
“TREM2 binding to Aβ promotes its phagocytosis by microglia, which in turn induces secretion of pro-inflammatory cytokines IL-6 and CCL3, increases microglial proliferation, migration and apoptosis and reduces intracellular K+ concentrations [31, 36].”
From Microglial function, INPP5D/SHIP1 signaling, and NLRP3 inflammasome activation: implications for Alzheimer’s disease (2023) · cites this paper as [31]
The Results sections on cytokine secretion and in vivo microglial responses report TREM2-dependent IL-6 and CCL3 secretion, migration, proliferation, and apoptosis after Aβ exposure (page numbers unavailable). But the Results section on Aβ degradation says TREM2 deletion had little effect on phagocytic uptake; it affected degradation instead. That section reports K+ currents and membrane potential, not a reduction in intracellular K+ concentration. (LLM, conf=0.90)
Experimental — accuracy not yet measuredTREM2 ligands include zwitterionic and anionic phospholipids, glycolipids, apoptotic cells, lipoproteins such as HDL, LDL, APOE and APOJ/CLU, as well as Aβ.
“TREM2 ligands include zwitterionic and anionic phospholipids, glycolipids, apoptotic cells, lipoproteins such as HDL, LDL, APOE and APOJ/CLU, as well as Aβ [30, 31].”
From Microglial function, INPP5D/SHIP1 signaling, and NLRP3 inflammasome activation: implications for Alzheimer’s disease (2023) · cites this paper as [31]
The Results report TREM2 binding to Aβ oligomers, and the Introduction and Discussion identify lipids and ApoE as TREM2 ligands. The copy does not establish the more specific lipid classes or HDL and LDL as ligands. It describes TREM2-mediated clearance of apoptotic debris, not binding to apoptotic cells; CLU/APOJ appears in the title of a cited study rather than in this paper’s findings. (LLM, conf=0.87)
Experimental — accuracy not yet measured
TREM2 can be directly bound and activated by Aβ, after which it mediates Aβ phagocytosis as well as Aβ-dependent microglial activation, cytokine production and secretion.
“TREM2 can be directly bound and activated by Aβ, after which it mediates Aβ phagocytosis as well as Aβ-dependent microglial activation, cytokine production and secretion as previously mentioned [31].”
From Microglial function, INPP5D/SHIP1 signaling, and NLRP3 inflammasome activation: implications for Alzheimer’s disease (2023) · cites this paper as [31]
The Results sections on Aβ binding and downstream signaling support direct binding, Aβ-triggered TREM2 signaling, microglial activation, and cytokine expression and release. But the Results section on Aβ degradation reports that TREM2 deletion had little effect on phagocytic uptake of Aβ; it impaired Aβ degradation instead. Page numbers were not provided in our copy. (LLM, conf=0.90)
Experimental — accuracy not yet measuredTREM2 interaction with Aβ can trigger Aβ-mediated inflammation and exacerbate Aβ deposition, linking TREM2 with a pro-inflammatory and even detrimental role depending on context and disease stage.
“While TREM2 function has been classically considered anti-inflammatory and protective in AD, its interaction with Aβ can trigger Aβ-mediated inflammation and exacerbate Aβ deposition, ultimately linking TREM2 with a pro-inflammatory and even a detrimental role depending on the context and disease stage [31, 36].”
From Microglial function, INPP5D/SHIP1 signaling, and NLRP3 inflammasome activation: implications for Alzheimer’s disease (2023) · cites this paper as [31]
The Results (page unavailable) report that TREM2–Aβ interactions trigger microglial activation and cytokine release, supporting the inflammation component. The Discussion (page unavailable) reports that TREM2 deletion reduced plaque load early but worsened deposition late in an APP/PS1 mouse model. It does not establish that the TREM2–Aβ interaction itself exacerbates deposition; the authors say its mechanism in Aβ pathology remains unresolved. (LLM, conf=0.87)
Experimental — accuracy not yet measuredCD36 binds oAβ and contributes to AD pathogenesis by regulating cerebral inflammation in microglia.
“CD36 can bind to oAβ and contributes to AD pathogenesis by regulating cerebral inflammation in microglia [341].”
From Molecular and cellular mechanisms underlying the pathogenesis of Alzheimer’s disease (2020) · cites this paper as [341]
TREM2 is an amyloid-β receptor with a higher affinity for amyloid-β oligomers than monomers.
“TREM2 was recently identified as an amyloid-β receptor with a higher affinity for amyloid-β oligomers than monomers50.”
From Interplay between innate immunity and Alzheimer disease: APOE and TREM2 in the spotlight (2018) · cites this paper as [50]
Apolipoproteins, lipids and Aβ itself act as ligands of TREM2 to facilitate microglial phagocytosis and clearance of Aβ and apoptotic neurons.
“Recently, it was further shown that apolipoproteins, lipids and Aβ itself acted as ligands of TREM2 to facilitate microglial phagocytosis and clearance of Aβ and apoptotic neurons (32–35).”
From <i>Trem2</i> promotes anti-inflammatory responses in microglia and is suppressed under pro-inflammatory conditions (2020) · cites this paper as [34]
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Cites
The amyloid hypothesis of Alzheimer's disease at 25 years
Selkoe, D. J., & Hardy, J. (2016) · EMBO Molecular Medicine · doi:10.15252/emmm.201606210 · Cited by 6,164 · 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
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
<i>TREM2</i> 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
Variant of <i>TREM2</i> 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
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
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
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
Linking lipids to Alzheimer's disease: cholesterol and beyond
Di Paolo, G., & Kim, T.-W. (2011) · Nature Reviews Neuroscience · doi:10.1038/nrn3012 · Cited by 972 · see citing works
Chishti, M. A., Yang, D.-S., Janus, C., Phinney, A. L., Horne, P., Pearson, J., Strome, R., Zuker, N., Loukides, J., French, J., et al. (2001) · Journal of Biological Chemistry · doi:10.1074/jbc.m100710200 · Cited by 955 · see citing works
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
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
The Ubiquitin Code in the Ubiquitin-Proteasome System and Autophagy
Kwon, Y. T., & Ciechanover, A. J. (2017) · Trends in Biochemical Sciences · doi:10.1016/j.tibs.2017.09.002 · Cited by 815 · see citing works
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
Coupled Proliferation and Apoptosis Maintain the Rapid Turnover of Microglia in the Adult Brain
Askew, K., Li, K., Olmos-Alonso, A., Garcia-Moreno, F., Liang, Y., Richardson, P., Tipton, T., Chapman, M. A., Riecken, K., Beccari, S., et al. (2017) · Cell Reports · doi:10.1016/j.celrep.2016.12.041 · Cited by 726 · see citing works
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
ApoE and Aβ in Alzheimer’s Disease: Accidental Encounters or Partners?
Kanekiyo, T., Xu, H., & Bu, G. (2014) · Neuron · doi:10.1016/j.neuron.2014.01.045 · Cited by 608 · see citing works
Self-citationApolipoprotein 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
Self-citationLate onset Alzheimer’s disease genetics implicates microglial pathways in disease risk
Efthymiou, A. G., & Goate, A. M. (2017) · Molecular Neurodegeneration · doi:10.1186/s13024-017-0184-x · Cited by 562 · 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
Reversing EphB2 depletion rescues cognitive functions in Alzheimer model
Cissé, M., Halabisky, B., Harris, J., Devidze, N., Dubal, D. B., Sun, B., Orr, A., Lotz, G., Kim, D. H., Hamto, P., et al. (2011) · Nature · doi:10.1038/nature09635 · Cited by 433 · see citing works
TREM2 in Neurodegenerative Diseases
Jay, T. R., von Saucken, V. E., & Landreth, G. E. (2017) · Molecular Neurodegeneration · doi:10.1186/s13024-017-0197-5 · Cited by 427 · see citing works
Kim, T., Vidal, G. S., Djurisic, M., William, C. M., Birnbaum, M. E., Garcia, K. C., Hyman, B. T., & Shatz, C. J. (2013) · Science · doi:10.1126/science.1242077 · Cited by 410 · 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
Self-citationTREM2 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
Doens, D., & Fernández, P. L. (2014) · Journal of Neuroinflammation · doi:10.1186/1742-2094-11-48 · Cited by 348 · see citing works
Coding variants in TREM2 increase risk for Alzheimer's disease
Jin, S. C., Benitez, B. A., Karch, C. M., Cooper, B., Skorupa, T., Carrell, D., Norton, J. B., Hsu, S., Harari, O., Cai, Y., et al. (2014) · Human Molecular Genetics · doi:10.1093/hmg/ddu277 · Cited by 314 · see citing works
TREM2and Neurodegenerative Disease
Reitz, C., & Mayeux, R. P. (2013) · New England Journal of Medicine · doi:10.1056/nejmc1306509 · Cited by 254 · see citing works
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
Chen, J., Carey, K. D., & Godowski, P. J. (1997) · Oncogene · doi:10.1038/sj.onc.1201039 · Cited by 209 · see citing works
Electrophysiological properties of microglial cells in normal and pathologic rat brain slices
Boucsein, C., Kettenmann, H., & Nolte, C. (2000) · European Journal of Neuroscience · doi:10.1046/j.1460-9568.2000.00100.x · Cited by 166 · see citing works
Pathological and physiological functions of presenilins
Vetrivel, K. S., Zhang, Y., Xu, H., & Thinakaran, G. (2006) · Molecular Neurodegeneration · doi:10.1186/1750-1326-1-4 · Cited by 158 · see citing works
Self-citationZhong, 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
Self-citationAnimal models of Alzheimer disease: historical pitfalls and a path forward
Cavanaugh, S. E. (2014) · ALTEX · doi:10.14573/altex.1310071 · Cited by 132 · see citing works
Zhao, Y., Tseng, I.-C., Heyser, C. J., Rockenstein, E., Mante, M., Adame, A., Zheng, Q., Huang, T., Wang, X., Arslan, P. E., et al. (2015) · Neuron · doi:10.1016/j.neuron.2015.08.020 · Cited by 98 · see citing works
Self-citationAn Update of Animal Models of Alzheimer Disease with a Reevaluation of Plaque Depositions
Lee, J. E., & Han, P. (2013) · Experimental Neurobiology · doi:10.5607/en.2013.22.2.84 · Cited by 97 · see citing works
Sorting Nexin 27 Regulates Aβ Production through Modulating γ-Secretase Activity
Wang, X., Huang, T., Zhao, Y., Zheng, Q., Thompson, R. C., Bu, G., Zhang, Y.-W., Hong, W., & Xu, H. (2014) · Cell Reports · doi:10.1016/j.celrep.2014.09.037 · Cited by 77 · see citing works
Self-citationCross-talk of membrane lipids and Alzheimer-related proteins
Walter, J., & van Echten‐Deckert, G. (2013) · Molecular Neurodegeneration · doi:10.1186/1750-1326-8-34 · Cited by 77 · see citing works
Zhu, B., Jiang, L., Huang, T., Zhao, Y., Liu, T., Zhong, Y., Li, X., Campos, A., Pomeroy, K., Masliah, E., et al. (2017) · Nature Communications · doi:10.1038/s41467-017-01799-4 · Cited by 71 · see citing works
Self-citationMa, L., Allen, M., Sakae, N., Ertekin-Taner, N., Graff-Radford, N. R., Dickson, D. W., Younkin, S. G., & Sevlever, D. (2016) · Molecular Neurodegeneration · doi:10.1186/s13024-016-0137-9 · Cited by 70 · see citing works
Huang, T. Y., Zhao, Y., Li, X., Wang, X., Tseng, I.-C., Thompson, R., Tu, S., Willnow, T. E., Zhang, Y.-W., & Xu, H. (2016) · The Journal of Neuroscience · doi:10.1523/jneurosci.0206-16.2016 · Cited by 69 · see citing works
Self-citationFranciosi, S., Ryu, J. K., Choi, H. B., Radov, L. A., Kim, S. U., & McLarnon, J. G. (2006) · Journal of Neuroscience · doi:10.1523/jneurosci.2490-06.2006 · Cited by 68 · see citing works
Wang, H. K., Park, U. J., Kim, S. Y., Lee, J. H., Kim, S. U., Gwag, B. J., & Lee, Y. B. (2008) · Journal of Neuroscience · doi:10.1523/jneurosci.4973-07.2008 · Cited by 55 · see citing works
Lam, D., & Schlichter, L. C. (2015) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2015.00185 · Cited by 45 · see citing works
Lam, D., & Schlichter, L. C. (2016) · Biophysical Journal · doi:10.1016/j.bpj.2015.11.1711 · Cited by 13 · see citing works
Flagged first, then by citations
Research works printed but not linked: 1
- Guerreiro R Hardy J 2013 TREM2 and neurodegenerative disease N Engl J Med 369 1569 1570 24143816
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Microglia in neurodegeneration
Hickman, S., Izzy, S., Sen, P., Morsett, L., & El Khoury, J. (2018) · Nature Neuroscience · doi:10.1038/s41593-018-0242-x · Cited by 1,710 · see citing works
Role of neuroinflammation in neurodegeneration development
Zhang, W., Xiao, D., Mao, Q., & Xia, H. (2023) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-023-01486-5 · Cited by 1,668 · see citing works
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
Molecular and cellular mechanisms underlying the pathogenesis of Alzheimer’s disease
Guo, T., Zhang, D., Zeng, Y., Huang, T. Y., Xu, H., & Zhao, Y. (2020) · Molecular Neurodegeneration · doi:10.1186/s13024-020-00391-7 · Cited by 994 · see citing works
Self-citationJohnson, E. C. B., Dammer, E. B., Duong, D. M., Ping, L., Zhou, M., Yin, L., Higginbotham, L. A., Guajardo, A., White, B., Troncoso, J. C., et al. (2020) · Nature Medicine · doi:10.1038/s41591-020-0815-6 · Cited by 1,001 · see citing works
TREM2 — a key player in microglial biology and Alzheimer disease
Ulland, T. K., & Colonna, M. (2018) · Nature Reviews Neurology · doi:10.1038/s41582-018-0072-1 · Cited by 735 · see citing works
Interplay between innate immunity and Alzheimer disease: APOE and TREM2 in the spotlight
Shi, Y., & Holtzman, D. M. (2018) · Nature Reviews Immunology · doi:10.1038/s41577-018-0051-1 · Cited by 595 · see citing works
A Quarter Century of APOE and Alzheimer’s Disease: Progress to Date and the Path Forward
Belloy, M. E., Napolioni, V., & Greicius, M. D. (2019) · Neuron · doi:10.1016/j.neuron.2019.01.056 · Cited by 570 · see citing works
New insights into the role of TREM2 in Alzheimer’s disease
Gratuze, M., Leyns, C. E. G., & Holtzman, D. M. (2018) · Molecular Neurodegeneration · doi:10.1186/s13024-018-0298-9 · Cited by 489 · see citing works
Heckmann, B. L., Teubner, B. J. W., Tummers, B., Boada-Romero, E., Harris, L., Yang, M., Guy, C. S., Zakharenko, S. S., & Green, D. R. (2019) · Cell · doi:10.1016/j.cell.2019.05.056 · Cited by 503 · see citing works
“…toll-like receptors (TLRs) (Gurley et al., 2008), Fc receptors (Fuller et al., 2014), Ig-superfamily receptors including TREM2 (Ulrich et al., 2014; Wang et al., 2016; Zhao et al., 2018), scavenger receptors (SR) (Wilkinson and El Khoury, 2012) and complement receptors (Doens and Fernandez, 2014).”
Tau and neuroinflammation in Alzheimer’s disease: interplay mechanisms and clinical translation
Chen, Y., & Yu, Y. (2023) · Journal of Neuroinflammation · doi:10.1186/s12974-023-02853-3 · Cited by 516 · see citing works
“TREM2 is a receptor for Aβ [121] and is exclusively expressed by microglia in the brain of mice and humans [122, 123].”
BackgroundTREM2 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
TREM2 Acts Downstream of CD33 in Modulating Microglial Pathology in Alzheimer's Disease
Griciuc, A., Patel, S., Federico, A. N., Choi, S. H., Innes, B. J., Oram, M. K., Cereghetti, G., McGinty, D., Anselmo, A., Sadreyev, R. I., et al. (2019) · Neuron · doi:10.1016/j.neuron.2019.06.010 · Cited by 378 · see citing works
Colonna, M. (2023) · Nature Reviews Immunology · doi:10.1038/s41577-023-00837-1 · Cited by 394 · see citing works
Zhong, L., Xu, Y., Zhuo, R., Wang, T., Wang, K., Huang, R., Wang, D., Gao, Y., Zhu, Y., Sheng, X., et al. (2019) · Nature Communications · doi:10.1038/s41467-019-09118-9 · Cited by 371 · see citing works
Self-citationMicroglia: Agents of the CNS Pro-Inflammatory Response
Rodríguez-Gómez, J. A., Kavanagh, E., Engskog-Vlachos, P., Engskog, M. K. R., Herrera, A. J., Espinosa-Oliva, A. M., Joseph, B., Hajji, N., Venero, J. L., & Burguillos, M. A. (2020) · Cells · doi:10.3390/cells9071717 · Cited by 365 · see citing works
Cai, Y., Liu, J., Wang, B., Sun, M., & Yang, H. (2022) · Frontiers in Immunology · doi:10.3389/fimmu.2022.856376 · Cited by 351 · 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
Microglia Phenotypes in Aging and Neurodegenerative Diseases
Wendimu, M. Y., & Hooks, S. B. (2022) · Cells · doi:10.3390/cells11132091 · Cited by 336 · see citing works
The identity and function of microglia in neurodegeneration
Song, W. M., & Colonna, M. (2018) · Nature Immunology · doi:10.1038/s41590-018-0212-1 · Cited by 308 · 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
Self-citationRestoring Wnt/β-catenin signaling is a promising therapeutic strategy for Alzheimer’s disease
Jia, L., Piña-Crespo, J., & Li, Y. (2019) · Molecular Brain · doi:10.1186/s13041-019-0525-5 · Cited by 288 · see citing works
Self-citationThe role of TREM2 in Alzheimer's disease and other neurodegenerative disorders
Carmona, S., Zahs, K., Wu, E., Dakin, K., Bras, J., & Guerreiro, R. (2018) · The Lancet Neurology · doi:10.1016/s1474-4422(18)30232-1 · Cited by 244 · see citing works
APOE and TREM2 regulate amyloid-responsive microglia in Alzheimer’s disease
Nguyen, A. T., Wang, K., Hu, G., Wang, X., Miao, Z., Azevedo, J. A., Suh, E., Van Deerlin, V. M., Choi, D., Roeder, K., et al. (2020) · Acta Neuropathologica · doi:10.1007/s00401-020-02200-3 · Cited by 241 · 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 and monocytes in inflammatory CNS disease: integrating phenotype and function
Spiteri, A. G., Wishart, C. L., Pamphlett, R., Locatelli, G., & King, N. J. C. (2022) · Acta Neuropathologica · doi:10.1007/s00401-021-02384-2 · Cited by 216 · see citing works
“Neuroprotective roles Microglia encircle Aβ plaques to prevent further growth and dissemination into the parenchyma [63], reducing damage to local neurites [295] Microglia may contribute to the phagocytic and enzymatic clearance of the Aβ plaque deposits [82] TREM2 expressed by damage-associated microglia is thought t…”
BackgroundLiu, W., Taso, O., Wang, R., Bayram, S., Graham, A. C., Garcia-Reitboeck, P., Mallach, A., Andrews, W. D., Piers, T. M., Botia, J. A., et al. (2020) · Human Molecular Genetics · doi:10.1093/hmg/ddaa209 · Cited by 214 · see citing works
“Recently, it was further shown that apolipoproteins and Aβ itself acted as ligands of TREM2 to facilitate microglial phagocytosis and clearance of Aβ and apoptotic neurons (Atagi et al. 2015; Yeh et al. 2016; Zhao et al. 2018).”
BackgroundMeilandt, 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
“…fraction of PS2APP;Trem2 ko brains could reflect direct deficits in the Trem2-mediated binding and clearance of oligomeric A 42 by microglia (Yeh et al., 2016; Lessard et al., 2018; Zhao et al., 2018), it could also reflect enhanced clearance of A 40 through other means, such as vascular efflux.”
BackgroundTREM2 dependent and independent functions of microglia in Alzheimer’s disease
Hou, J., Chen, Y., Grajales-Reyes, G., & Colonna, M. (2022) · Molecular Neurodegeneration · doi:10.1186/s13024-022-00588-y · Cited by 191 · see citing works
Loss of microglial SIRPα promotes synaptic pruning in preclinical models of neurodegeneration
Ding, X., Wang, J., Huang, M., Chen, Z., Liu, J., Zhang, Q., Zhang, C., Xiang, Y., Zen, K., & Li, L. (2021) · Nature Communications · doi:10.1038/s41467-021-22301-1 · Cited by 180 · see citing works
Xiang, X., Piers, T. M., Wefers, B., Zhu, K., Mallach, A., Brunner, B., Kleinberger, G., Song, W., Colonna, M., Herms, J., et al. (2018) · Molecular Neurodegeneration · doi:10.1186/s13024-018-0280-6 · Cited by 170 · 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
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
Self-citationDysregulated phosphoinositide 3-kinase signaling in microglia: shaping chronic neuroinflammation
Chu, E., Mychasiuk, R., Hibbs, M. L., & Semple, B. D. (2021) · Journal of Neuroinflammation · doi:10.1186/s12974-021-02325-6 · Cited by 152 · see citing works
Ewers, M., Biechele, G., Suárez‐Calvet, M., Sacher, C., Blume, T., Morenas‐Rodriguez, E., Deming, Y., Piccio, L., Cruchaga, C., Kleinberger, G., et al. (2020) · EMBO Molecular Medicine · doi:10.15252/emmm.202012308 · Cited by 133 · see citing works
Trem2 deletion enhances tau dispersion and pathology through microglia exosomes
Zhu, B., Liu, Y., Hwang, S., Archuleta, K., Huang, H., Campos, A., Murad, R., Piña-Crespo, J., Xu, H., & Huang, T. Y. (2022) · Molecular Neurodegeneration · doi:10.1186/s13024-022-00562-8 · Cited by 127 · see citing works
Self-citationNoncanonical function of an autophagy protein prevents spontaneous Alzheimer’s disease
Heckmann, B. L., Teubner, B. J. W., Boada-Romero, E., Tummers, B., Guy, C., Fitzgerald, P., Mayer, U., Carding, S., Zakharenko, S. S., Wileman, T., et al. (2020) · Science Advances · doi:10.1126/sciadv.abb9036 · Cited by 114 · see citing works
Advance of sporadic Alzheimer's disease animal models
Zhang, L., Chen, C., Mak, M. S., Lu, J., Wu, Z., Chen, Q., Han, Y., Li, Y., & Pi, R. (2020) · Medicinal Research Reviews · doi:10.1002/med.21624 · Cited by 116 · see citing works
TREM2 ectodomain and its soluble form in Alzheimer’s disease
Yang, J., Fu, Z., Zhang, X., Xiong, M., Meng, L., & Zhang, Z. (2020) · Journal of Neuroinflammation · doi:10.1186/s12974-020-01878-2 · Cited by 113 · see citing works
Distinct Signaling Pathways Regulate TREM2 Phagocytic and NFκB Antagonistic Activities
Yao, H., Coppola, K., Schweig, J. E., Crawford, F., Mullan, M., & Paris, D. (2019) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2019.00457 · Cited by 110 · see citing works
Desale, S. E., Chidambaram, H., & Chinnathambi, S. (2021) · Molecular Biomedicine · doi:10.1186/s43556-021-00036-1 · Cited by 99 · see citing works
Cellular Receptors of Amyloid β Oligomers (AβOs) in Alzheimer’s Disease
Mroczko, B., Groblewska, M., Litman-Zawadzka, A., Kornhuber, J., & Lewczuk, P. (2018) · International Journal of Molecular Sciences · doi:10.3390/ijms19071884 · Cited by 97 · see citing works
Terzioglu, G., & Young-Pearse, T. L. (2023) · Molecular Neurodegeneration · doi:10.1186/s13024-023-00674-9 · Cited by 95 · see citing works
Zheng, Q., Li, G., Wang, S., Zhou, Y., Liu, K., Gao, Y., Zhou, Y., Zheng, L., Zhu, L., Deng, Q., et al. (2021) · Science Advances · doi:10.1126/sciadv.abe1340 · Cited by 85 · see citing works
Self-citationArtificial intelligence for drug discovery and development in Alzheimer's disease
Qiu, Y., & Cheng, F. (2024) · Current Opinion in Structural Biology · doi:10.1016/j.sbi.2024.102776 · Cited by 83 · see citing works
Lista, S., Imbimbo, B. P., Grasso, M., Fidilio, A., Emanuele, E., Minoretti, P., López-Ortiz, S., Martín-Hernández, J., Gabelle, A., Caruso, G., et al. (2024) · Journal of Neuroinflammation · doi:10.1186/s12974-024-03163-y · Cited by 81 · see citing works
Su, Q., Li, T., He, P.-F., Lu, X.-C., Yu, Q., Gao, Q.-C., Wang, Z.-J., Wu, M.-N., Yang, D., & Qi, J.-S. (2021) · Alzheimer's Research & Therapy · doi:10.1186/s13195-020-00746-8 · Cited by 75 · see citing works
Dysregulated Wnt Signalling in the Alzheimer’s Brain
Aghaizu, N. D., Jin, H., & Whiting, P. J. (2020) · Brain Sciences · doi:10.3390/brainsci10120902 · Cited by 70 · see citing works
Ren, S., Yao, W., Tambini, M. D., Yin, T., Norris, K. A., & D'Adamio, L. (2020) · eLife · doi:10.7554/elife.57513 · Cited by 68 · see citing works
Microglia, Trem2, and Neurodegeneration
Shi, Q., Gutierrez, R. A., & Bhat, M. A. (2025) · The Neuroscientist · doi:10.1177/10738584241254118 · Cited by 69 · see citing works
Modulation of β-Amyloid Fibril Formation in Alzheimer’s Disease by Microglia and Infection
Brown, M. R., Radford, S. E., & Hewitt, E. W. (2020) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2020.609073 · Cited by 67 · see citing works
LILRB2-mediated TREM2 signaling inhibition suppresses microglia functions
Zhao, P., Xu, Y., Jiang, L.-L., Fan, X., Ku, Z., Li, L., Liu, X., Deng, M., Arase, H., Zhu, J.-J., et al. (2022) · Molecular Neurodegeneration · doi:10.1186/s13024-022-00550-y · Cited by 54 · see citing works
Self-citationFancy, N. N., Smith, A. M., Caramello, A., Tsartsalis, S., Davey, K., Muirhead, R. C. J., McGarry, A., Jenkyns, M. H., Schneegans, E., Chau, V., et al. (2024) · Acta Neuropathologica · doi:10.1007/s00401-024-02727-9 · Cited by 48 · see citing works
“…in AD depends specifically on microglial activation with β-amyloid, we generated snRNA transcriptomes of microglia obtained from neuro-pathologically defined AD donors carrying the TREM2 R47H variant allele, which is associated with reduced responsiveness of microglia to β-amyloid [68, 83].”
MethodThe role of TREM2 in Alzheimer’s disease: from the perspective of Tau
Huang, W., Huang, J., Huang, N., & Luo, Y. (2023) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2023.1280257 · Cited by 49 · see citing works
McFarland, K. N., & Chakrabarty, P. (2022) · Neurotherapeutics · doi:10.1007/s13311-021-01179-3 · Cited by 48 · see citing works
Ren, S., Breuillaud, L., Yao, W., Yin, T., Norris, K. A., Zehntner, S. P., & D’Adamio, L. (2021) · Journal of Biological Chemistry · doi:10.1074/jbc.ra120.016395 · Cited by 47 · see citing works
Genetic risk factors for Alzheimer disease: emerging roles of microglia in disease pathomechanisms
Takatori, S., Wang, W., Iguchi, A., & Tomita, T. (2019) · Advances in Experimental Medicine and Biology · doi:10.1007/978-3-030-05542-4_5 · Cited by 44 · see citing works
Jana, A., Wang, X., Leasure, J. W., Magana, L., Wang, L., Kim, Y.-M., Dodiya, H., Toth, P. T., Sisodia, S. S., & Rehman, J. (2022) · Scientific Reports · doi:10.1038/s41598-022-20889-y · Cited by 43 · see citing works
Microglial phagocytosis in Alzheimer disease
Brown, G. C., St George-Hyslop, P., Paolicelli, R. C., & Lemke, G. (2026) · Nature Reviews Neurology · doi:10.1038/s41582-025-01162-y · Cited by 36 · see citing works
Etxeberria, A., Shen, Y.-A. A., Vito, S., Silverman, S. M., Imperio, J., Lalehzadeh, G., Soung, A. L., Du, C., Xie, L., Choy, M. K., et al. (2024) · The Journal of Neuroscience · doi:10.1523/jneurosci.2347-23.2024 · Cited by 34 · see citing works
Solomon, S., Sampathkumar, N. K., Carre, I., Mondal, M., Chennell, G., Vernon, A. C., Ruepp, M.-D., & Mitchell, J. C. (2022) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-022-04473-1 · Cited by 23 · see citing works
“Several other polymorphisms implicated as risk factors in AD, such as the R47H TREM2 mutation, result in alterations to microglial phagocytic capacity that lead to reduced clearance of Aβ aggregates and neuronal decline [27, 28].”
BackgroundLi, X., Tang, X., Zeng, J., Duan, L., Hou, Z., Li, L., Guo, Y., Chai, C., Liu, J., Wang, Y., et al. (2026) · Cell · doi:10.1016/j.cell.2025.12.020 · Cited by 21 · see citing works
Self-citationSánchez‐Ruiz de Gordoa, J., Erro, M. E., Vicuña‐Urriza, J., Zelaya, M. V., Tellechea, P., Acha, B., Zueco, S., Urdánoz‐Casado, A., Roldán, M., Blanco‐Luquin, I., et al. (2020) · Movement Disorders · doi:10.1002/mds.27992 · Cited by 18 · see citing works
- Authors
- Zhao, Y., Wu, X., Li, X., Jiang, L.-L., Gui, X., Liu, Y., Sun, Y., Zhu, B., Piña-Crespo, J. C., Zhang, M., Zhang, N., Chen, X., Bu, G., An, Z., Huang, T. Y., & Xu, H.
- Affiliations
- Sanford Burnham Prebys Medical Discovery Institute (US)
- Fujian Medical University (CN)
- Brown Foundation Institute of Molecular Medicine for the Prevention of Human Diseases (US)
- Xiamen University (CN)
- Mayo Clinic (US)
- Corresponding author
- Xu, Huaxi
- ORCID
- Venue
- Neuron
- Publisher
- Elsevier BV
- Published
- 2018-03
- Volume
- 97
- Issue
- 5
- Pages
- 1023-1031.e7
- ISSN
- 0896-6273 (ISSN-L)
- PMC
- PMC5889092
- OpenAlex
- W2793872352
- Cited by
- 763
- References
- 45
- Citations by year
- 2026: 77 · 2025: 100 · 2024: 104 · 2023: 98 · 2022: 107 · 2021: 93 · 2020: 93 · 2019: 54 · 2018: 36
- FWCI
- 31.07
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Neuron (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Rare & Special e-Zone (The Hong Kong University of Science and Technology) (submittedVersion)
- Funders
- National Natural Science Foundation of China (U1505227, 81771163, U1405222)
- National Institutes of Health (R21 AG048519, R01 NS046673, RF1 AG056130, RF1 AG056114, R01 AG044420, R01 AG021173, R01 AG038710)
- Cure Alzheimer's Fund
- Welch Foundation (AU-0042-20030616)
- 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, amyloid-beta, Alzheimer's disease, microglia, DAP12, Syk, GSK3β, microglial migration, cytokine production, amyloid degradation, ligand-receptor interactions
- MeSH terms
- Aged, Aged, 80 and over, Alzheimer Disease, Animals, Brain, Cells, Cultured, Double-Blind Method, Female, Humans, Male, Membrane Glycoproteins, Mice, Inbred C3H, Mice, Inbred C57BL, Mice, Transgenic, Protein Binding, Receptors, Immunologic, Amyloid beta-Peptides, Microglia, Mice, Knockout, Mice, HEK293 Cells
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