Differential effects of partial and complete loss of TREM2 on microglial injury response and tauopathy
Open accessAbstract
Alzheimer’s disease (AD), the most common form of dementia, is characterized by the abnormal accumulation of amyloid plaques and hyperphosphorylated tau aggregates, as well as microgliosis. Hemizygous missense variants in Triggering Receptor Expressed on Myeloid Cells 2 ( TREM2 ) are associated with elevated risk for developing late-onset AD. These variants are hypothesized to result in loss of function, mimicking TREM2 haploinsufficiency. However, the consequences of TREM2 haploinsufficiency on tau pathology and microglial function remain unknown. We report the effects of partial and complete loss of TREM2 on microglial function and tau-associated deficits. In vivo imaging revealed that microglia from aged TREM2-haploinsufficient mice show a greater impairment in their injury response compared with microglia from aged TREM2-KO mice. In transgenic mice expressing mutant human tau, TREM2 haploinsufficiency, but not complete loss of TREM2, increased tau pathology. In addition, whereas complete TREM2 deficiency protected against tau-mediated microglial activation and atrophy, TREM2 haploinsufficiency elevated expression of proinflammatory markers and exacerbated atrophy at a late stage of disease. The differential effects of partial and complete loss of TREM2 on microglial function and tau pathology provide important insights into the critical role of TREM2 in AD pathogenesis.
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Complete deficiency in TREM2 protected PS19 mice against tau-mediated microgliosis and brain atrophy.
“a complete deficiency in TREM2 protected PS19 mice against tau-mediated microgliosis and brain atrophy [18].”
From TREM2-Deficient Microglia Attenuate Tau Spreading In Vivo (2023) · cites this paper as [18]
In the Results section on atrophy and microgliosis (page unavailable), complete TREM2 deficiency protected P301S mice against hippocampal atrophy. The same section reports only a trend toward reduced microglial density, although it found fewer morphological signs of microglial activation. Thus, saying it protected against microgliosis overstates the density finding. (LLM, conf=0.86)
Experimental — accuracy not yet measuredTREM2 haploinsufficiency (50% reduction in TREM2 levels) increased tau pathology.
“TREM2 haploinsufficiency (50% reduction in TREM2 levels) increased tau pathology [18].”
From TREM2-Deficient Microglia Attenuate Tau Spreading In Vivo (2023) · cites this paper as [18]
The Results section, “TREM2 Haploinsufficiency Exacerbates Tau Pathology in P301S Mice,” reports significantly increased tau-pathology staining in P301S mice with one TREM2 allele compared with mice with two. The passages identify the model as TREM2 haploinsufficiency, but do not establish the parenthetical claim that TREM2 levels were reduced by exactly 50%. (LLM, conf=0.86)
Experimental — accuracy not yet measuredManipulation of Trem2, Tyrobp, Cx3cl1/Cx3cr1, IL1β, and IFN-γ have opposing effects on amyloid and tau pathologies.
“Indeed, manipulation of expression of Trem2, Tyrobp, Cx3cl1/Cx3cr1, IL1β, and IFN-γ have all been shown to have opposing effects on amyloid and tau pathologies [49–51, 55–65].”
From Deletion of Abi3/Gngt2 influences age-progressive amyloid β and tau pathologies in distinctive ways (2022) · cites this paper as [49]
The Results section reports that partial loss of TREM2 increased tau pathology in P301S mice, whereas complete loss did not. The Discussion compares inflammatory responses in amyloid and tau models, but does not show opposing effects on amyloid versus tau pathology. This paper also does not establish the claimed effects for the other listed genes and cytokines. (LLM, conf=0.85)
Experimental — accuracy not yet measuredThe dichotomy of immune effects on amyloid and tau has been demonstrated in multiple models of Trem2 and Tyrobp.
“More recently, this dichotomy has been elegantly demonstrated in multiple models of Trem2 and Tyrobp [49–51, 55–59].”
From Deletion of Abi3/Gngt2 influences age-progressive amyloid β and tau pathologies in distinctive ways (2022) · cites this paper as [49]
The Discussion (page unavailable) says TREM2 haploinsufficiency may differentially modulate inflammation in amyloid and tau pathology, drawing on this paper’s tau-model findings and reports from amyloid models. But this study does not itself demonstrate the dichotomy across multiple amyloid and tau models, and the cited passages do not establish it for Tyrobp. (LLM, conf=0.84)
Experimental — accuracy not yet measuredHaploinsufficiency and total deficiency of TREM2 can lead to opposite effects.
“Further complicating matters, haploinsufficiency and total deficiency of TREM2 can lead to opposite effects,44”
From Microglial <i>INPP5D</i> limits plaque formation and glial reactivity in the PSAPP mouse model of Alzheimer's disease (2023) · cites this paper as [44]
In the PS19 model, a 50% decrease in TREM2 but not a total reduction enhanced tau phosphorylation and aggregation.
“In another study that evaluated the effect of TREM2 loss-of-function in the PS19 model, a 50% decrease in TREM2 but not a total reduction enhanced tau phosphorylation and aggregation [18].”
From TREM2-Deficient Microglia Attenuate Tau Spreading In Vivo (2023) · cites this paper as [18]
Recent studies have identified a role for gene dosage in microglial genes, including TREM2, whereby partial and complete loss of gene expression resulted in divergent phenotypic consequences.
“Surprisingly, recent studies have identified a role for gene dosage in microglial genes, including TREM2, whereby partial and complete loss of gene expression resulted in divergent phenotypic consequences, emphasizing the importance of exploring total PLCG2 loss.”
From PLCG2 modulates TREM2 expression and signaling in response to Alzheimer's disease pathology (2025) · cites this paper as [31]
Impaired or absent Trem2 function attenuates the microglial response to amyloid pathology by regulating microglial number around plaques, regulating microglial activity, and restricting neuritic damage.
“Recent important studies have also shown that impaired/absent Trem2 function attenuates the microglial response to amyloid pathology by regulating microglial number around plaques, regulating microglial activity, and restricting neuritic damage (37,61,84–87,95–99).”
From <i>Trem2</i> promotes anti-inflammatory responses in microglia and is suppressed under pro-inflammatory conditions (2020) · cites this paper as [97]
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BackgroundInfluentialTREM2: 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
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
Dong, Y., Yu, H., Li, X., Bian, K., Zheng, Y., Dai, M., Feng, X., Sun, Y., He, Y. T., Yu, B., et al. (2022) · Journal of Neuroinflammation · doi:10.1186/s12974-022-02567-y · Cited by 123 · see citing works
“In the TauP301S tauopathy mouse model, microglial inactivation attenuates neuroinflammation and tau-mediated neurodegeneration, indicating that microglia contribute to neuronal death in models of tau-mediated neurodegeneration [22, 23].”
BackgroundProkop, S., Miller, K. R., Labra, S. R., Pitkin, R. M., Hoxha, K., Narasimhan, S., Changolkar, L., Rosenbloom, A., Lee, V. M.-Y., & Trojanowski, J. Q. (2019) · Acta Neuropathologica · doi:10.1007/s00401-019-02048-2 · Cited by 119 · see citing works
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
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
“TREM2 deletion protected against atrophy and reduced inflammatory responses in P301S mice [99].”
BackgroundA cell therapy approach to restore microglial Trem2 function in a mouse model of Alzheimer’s disease
Yoo, Y., Neumayer, G., Shibuya, Y., Mader, M. M.-D., & Wernig, M. (2023) · Cell Stem Cell · doi:10.1016/j.stem.2023.07.006 · Cited by 109 · 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
TREM2-independent microgliosis promotes tau-mediated neurodegeneration in the presence of ApoE4.
Gratuze, M., Schlachetzki, J. C. M., D’Oliveira Albanus, R., Jain, N., Novotny, B., Brase, L., Rodriguez, L., Mansel, C., Kipnis, M., O’Brien, S., et al. (2023) · Neuron · doi:10.1016/j.neuron.2022.10.022 · Cited by 115 · see citing works
Role of Microglial Cells in Alzheimer’s Disease Tau Propagation
Španić, E., Horvat, L. L., Hof, P. R., & Šimić, G. (2019) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2019.00271 · Cited by 107 · see citing works
Jiang, S., Maphis, N. M., Binder, J., Chisholm, D., Weston, L., Duran, W., Peterson, C., Zimmerman, A., Mandell, M. A., Jett, S. D., et al. (2021) · Cell Reports · doi:10.1016/j.celrep.2021.109720 · Cited by 92 · see citing works
“…made by few previous reports on the colocalization of NLRP3, IL-1 β , and caspase-1 with pTau in the human AD brains (Ahmed et al., 2017) and significantly elevated levels of proinflammatory cytokines TNF-α , IL-1 α , and IL-1 β in the P301S mouse model of tauopathy (Sayed et al., 2018).”
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
“…Aβ pathology (Wang et al., 2016; Lee et al., 2018), hyperphosphorylation and aggregation of tau (Bemiller et al., 2017; Leyns and Holtzman, 2017; Sayed et al., 2018), microgliosis and inflammation in AD (Zhong et al., 2015, 2017b; Zheng et al., 2016; Jay et al., 2017a; Ulrich et al., 2017).”
BackgroundTauopathies: Deciphering Disease Mechanisms to Develop Effective Therapies
Silva, M. C., & Haggarty, S. J. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21238948 · Cited by 87 · see citing works
Carling, G. K., Fan, L., Foxe, N. R., Norman, K., Wong, M. Y., Zhu, D., Corona, C., Razzoli, A., Yu, F., Yarahmady, A., et al. (2024) · Neuron · doi:10.1016/j.neuron.2024.09.006 · Cited by 89 · see citing works
Senescent Microglia: The Key to the Ageing Brain?
Greenwood, E. K., & Brown, D. R. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22094402 · Cited by 84 · see citing works
“TREM2 knockout or dysfunction has been linked to a shift towards glycolytic metabolism and away from the more efficient oxidative phosphorylation [69,156,157].”
BackgroundBenítez, D. P., Jiang, S., Wood, J. I., Wang, R., Hall, C. M., Peerboom, C., Wong, N. S. M., Stringer, K. M., Vitanova, K. S., Smith, V. C., et al. (2021) · Molecular Neurodegeneration · doi:10.1186/s13024-021-00457-0 · Cited by 79 · see citing works
“Conversely, complete Trem2 deficiency is protective in the tau mice [59].”
BackgroundMicroglia and Wnt Pathways: Prospects for Inflammation in Alzheimer’s Disease
Yang, Y., & Zhang, Z. (2020) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2020.00110 · Cited by 76 · see citing works
Lee, S.-H., Rezzonico, M. G., Friedman, B. A., Huntley, M. H., Meilandt, W. J., Pandey, S., Chen, Y.-J. J., Easton, A. E., Modrusan, Z. D., Hansen, D. V., et al. (2021) · Cell Reports · doi:10.1016/j.celrep.2021.110158 · Cited by 76 · see citing works
Schoch, K. M., Ezerskiy, L. A., Morhaus, M. M., Bannon, R. N., Sauerbeck, A. D., Shabsovich, M., Jafar-nejad, P., Rigo, F., & Miller, T. M. (2021) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2100356118 · Cited by 78 · see citing works
“However, TREM2 function and microglial activation also may depend on other factors, such as age (20–22), disease insult or injury (23–25), gene dosage (26), and the presence of Aβ and/or tau pathology (19, 27–29), which together reveal specific contexts”
BackgroundCastranio, E. L., Hasel, P., Haure‐Mirande, J., Ramirez Jimenez, A. V., Hamilton, B. W., Kim, R. D., Glabe, C. G., Wang, M., Zhang, B., Gandy, S., et al. (2023) · Alzheimer's & Dementia · doi:10.1002/alz.12821 · Cited by 74 · see citing works
“Further complicating matters, haploinsufficiency and total deficiency of TREM2 can lead to opposite effects, 44 and differing outcomes have also been reported with microglial depletion.”
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
“…tau pathology and seeding but decreased tau-mediated neurodegeneration, whereas TREM2 haplodeficiency aggravates neuroinflammation and exacerbates tau pathology and brain atrophy, showing a complex role of TREM2 in the pathogenic process of AD (Leyns et al., 2017, 2019; Sayed et al., 2018).”
BackgroundTREM2 and sTREM2 in Alzheimer’s disease: from mechanisms to therapies
Zhang, L., Xiang, X., Li, Y., Bu, G., & Chen, X. (2025) · Molecular Neurodegeneration · doi:10.1186/s13024-025-00834-z · Cited by 78 · see citing works
“However, heterozygous TREM2 deficiency shows the opposite effect, intensifying tau pathology, brain atrophy, and pro-inflammatory responses in the same model [103].”
Fang, K., Li, H., Chen, X.-X., Gao, X., Huang, L.-L., Du, A.-Q., Jiang, C., Li, H., & Ge, J. (2020) · Frontiers in Pharmacology · doi:10.3389/fphar.2020.00518 · Cited by 72 · 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
“However, the roles for Trem2 in pure tauopathy mouse models appear to be more complex and somewhat contradictory (Bemiller and others 2017; Sayed and others 2018).”
Microglia: Friend and foe in tauopathy
Odfalk, K. F., Bieniek, K. F., & Hopp, S. C. (2022) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2022.102306 · Cited by 60 · see citing works
Audrain, M., Haure‐Mirande, J., Mleczko, J., Wang, M., Griffin, J. K., St George‐Hyslop, P. H., Fraser, P., Zhang, B., Gandy, S., & Ehrlich, M. E. (2021) · Alzheimer's & Dementia · doi:10.1002/alz.12256 · Cited by 65 · see citing works
Delizannis, A. T., Nonneman, A., Tsering, W., Bondt, A. D., den Wyngaert, I. V., Zhang, B., Meymand, E. S., Olufemi, M. F., Koivula, P. P., Maimaiti, S., et al. (2021) · Acta Neuropathologica Communications · doi:10.1186/s40478-021-01251-1 · Cited by 67 · see citing works
“A somewhat similar trend was previously observed, where TREM2 haploinsufficiency was found to be more detrimental than TREM2 KO in the development of tau pathology in a mouse model with mutant tau over-expression [35].”
ResultRole of TREM2 in Alzheimer’s Disease: A Long Road Ahead
Kulkarni, B., Kumar, D., Martins, N. A., & Sellamuthu, S. (2021) · Molecular Neurobiology · doi:10.1007/s12035-021-02477-9 · Cited by 52 · see citing works
Codocedo, J. F., Mera-Reina, C., Bor-Chian Lin, P., Fallen, P. B., Puntambekar, S. S., Casali, B. T., Jury-Garfe, N., Martinez, P., Lasagna-Reeves, C. A., & Landreth, G. E. (2024) · Cell Reports · doi:10.1016/j.celrep.2024.114488 · Cited by 52 · see citing works
“58 Moreover, PLCG2, another important AD risk gene, can regulate divergent microglial functions via Trem2 or TLR association, 59 reinforcing the idea that many molecular players can drive microglial phenotypes depending not only on its enzymatic activity but also on its cellular localization and…”
The role of microglia in Alzheimer's disease and progress of treatment
Guan, Y.-H., Zhang, L.-W., Wang, S.-Y., Deng, Y.-D., Zhou, H.-S., Chen, D., & Zhang, L. (2022) · Ibrain · doi:10.1002/ibra.12023 · Cited by 48 · see citing works
“9 Our aim is to better elucidate the mediating role of microglia in the treat-ment of AD by exploring the mechanism of microglia in AD, and to summarize relevant targets and drugs.”
Tran, K. M., Kawauchi, S., Kramár, E. A., Rezaie, N., Liang, H. Y., Sakr, J., Gómez-Arboledas, Á., Arreola, M. A., da Cunha, C., Phan, J., et al. (2023) · Molecular Neurodegeneration · doi:10.1186/s13024-023-00598-4 · Cited by 50 · see citing works
“Crossing of these mice with the PS19 mouse model of tauopathy found that the R47H variant exacerbates damage and inflammation and does not function as a loss of function variant [18], unlike similar crosses of PS19 mice with the human BAC TREM2R47H model which actually protected against microglia activation and subseq…”
You, J., Youssef, M., Santos, J. R., Lee, J., & Park, J. (2023) · Biology · doi:10.3390/biology12101307 · Cited by 56 · see citing works
The 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
Penney, J., Ralvenius, W. T., Loon, A. R., Cerit, O., Dileep, V., Milo, B., Pao, P., Woolf, H., & Tsai, L. (2023) · Glia · doi:10.1002/glia.24485 · Cited by 51 · see citing works
“Impaired microglial responses to laser-induced injury have been reported in the brains of TREM2 heterozygous and homozygous KO mice (Mazaheri et al., 2017; Sayed et al., 2018).”
BackgroundToral-Ríos, D., Long, J. M., Ulrich, J. D., Yu, J., Strickland, M. R., Han, X., Holtzman, D. M., Cashikar, A. G., & Paul, S. M. (2024) · The Journal of Experimental Medicine · doi:10.1084/jem.20232000 · Cited by 47 · see citing works
Gao, X.-R., Chen, Z., Fang, K., Xu, J.-X., & Ge, J.-F. (2021) · Lipids in Health and Disease · doi:10.1186/s12944-021-01590-x · Cited by 47 · see citing works
Harnessing Immunoproteostasis to Treat Neurodegenerative Disorders
Golde, T. E. (2019) · Neuron · doi:10.1016/j.neuron.2019.02.027 · Cited by 45 · see citing works
Neuronal ApoE4 in Alzheimer’s disease and potential therapeutic targets
Zhang, L., Xia, Y., & Gui, Y. (2023) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2023.1199434 · Cited by 41 · see citing works
Neuroimmunometabolism: A New Pathological Nexus Underlying Neurodegenerative Disorders
Mitra, S., Banik, A., Saurabh, S., Maulik, M., & Khatri, S. (2022) · Journal of Neuroscience · doi:10.1523/jneurosci.0998-21.2022 · Cited by 44 · see citing works
“Surprisingly, TREM2 haploinsufficiency increases tau pathology and inflammatory responses more than complete knockdown of TREM2 in a mouse model of tauopathy, suggesting a dynamic role of TREM2 in regulating neuroinflammation by a probable compensatory mechanism in microglia ( Sayed et al., 2018).”
The role of TREM2 in Alzheimer's disease; evidence from transgenic mouse models
Karanfilian, L., Tosto, M. G., & Malki, K. (2019) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2019.09.004 · Cited by 40 · see citing works
Glial cells and adaptive immunity in frontotemporal dementia with tau pathology
Hartnell, I. J., Blum, D. L., Nicoll, J. A. R., Dorothée, G., & Boche, D. (2020) · Brain · doi:10.1093/brain/awaa457 · Cited by 40 · see citing works
The Emerging Roles and Therapeutic Potential of Soluble TREM2 in Alzheimer’s Disease
Zhong, L., & Chen, X. (2019) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2019.00328 · Cited by 40 · see citing works
“Other studies have evaluated the impacts of Trem2 deficiency, TREM2 mutation, or human TREM2 expression in amyloid or tau mouse models (Ulrich et al., 2014; Jay et al., 2015; Wang et al., 2015; Bemiller et al., 2017; Leyns et al., 2017, 2019; Cheng-Hathaway et al., 2018; Lee et al., 2018; Sayed et al., 2018; Song et a…”
BackgroundCarrier, M., Šimončičová, E., St‐Pierre, M., McKee, C., & Tremblay, M. (2021) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2021.749737 · Cited by 37 · see citing works
Reduction of the RNA Binding Protein TIA1 Exacerbates Neuroinflammation in Tauopathy
LeBlang, C. J., Medalla, M., Nicoletti, N. W., Hays, E. C., Zhao, J., Shattuck, J. E., Cruz, A. L., Wolozin, B. L., & Luebke, J. I. (2020) · Frontiers in Neuroscience · doi:10.3389/fnins.2020.00285 · Cited by 38 · see citing works
“…occurs in the hippocampus of P301S transgenic mice, with microglial reactivity beginning as early as 4 months of age, and increasing in severity with disease progression (Yoshiyama et al., 2007; López-González et al., 2015; Schweig et al., 2017; Dejanovic et al., 2018; Sayed et al., 2018).”
Denver, P., D’Adamo, H., Hu, S., Zuo, X., Zhu, C., Okuma, C., Kim, P., Castro, D., Jones, M. R., Leal, C. D. R., et al. (2019) · Frontiers in Physiology · doi:10.3389/fphys.2019.01269 · Cited by 36 · see citing works
“Introduction of human tau or frontotemporal tau dementia mutations can lead to development of neurofibrillary tangles, but those models do not precisely recapitulate pathogenesis in AD, in part because AD patients do not have tau mutations driving tauopathy (Sydow et al., 2011; Sayed et al., 2018).”
BackgroundMicroglial TREM2 at the Intersection of Brain Aging and Alzheimer’s Disease
Qu, W., & Li, L. (2021) · The Neuroscientist · doi:10.1177/10738584211040786 · Cited by 37 · 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
Konishi, H., & Kiyama, H. (2020) · Neurochemistry International · doi:10.1016/j.neuint.2020.104878 · Cited by 33 · see citing works
TREM2 and Microglia Contribute to the Synaptic Plasticity: from Physiology to Pathology
Yu, C.-J., Wang, M., Ruiyang, L., Wei, T., Yang, H.-C., Yin, Y., Mi, Y., Qin, Q., & Tang, Y. (2022) · Molecular Neurobiology · doi:10.1007/s12035-022-03100-1 · Cited by 33 · see citing works
TREM2 in Alzheimer's disease: Structure, function, therapeutic prospects, and activation challenges
Zgórzyńska, E. (2024) · Molecular and Cellular Neuroscience · doi:10.1016/j.mcn.2024.103917 · Cited by 28 · see citing works
Ghimire, A., Rehman, S. A., Subhani, A., Khan, M. A., Rahman, Z., Iqubal, M. K., & Iqubal, A. (2025) · hLife · doi:10.1016/j.hlife.2024.11.006 · Cited by 30 · see citing works
“TREM-2, the triggering receptor 2 on myeloid cells, whose soluble form is cerebrospinal fl uid (CSF) soluble TREM-2, is positively correlated with CSF PGRN [78].”
Roles of TREM2 in Alzheimer’s disease
Qi, X., Zhu, K., Ke, W., Wang, J., Mao, S., & Chen, G. (2025) · Translational Neurodegeneration · doi:10.1186/s40035-025-00515-3 · Cited by 36 · see citing works
“Conversely, while complete KO results in microglial dysfunction, the complete absence of TREM2 may trigger compensatory mechanisms that mitigate inflammatory responses [361, 365].”
InfluentialVautheny, A., Duwat, C., Aurégan, G., Joséphine, C., Hérard, A.-S., Jan, C., Mitja, J., Gipchtein, P., Gaillard, M.-C., Buée, L., et al. (2021) · Neurobiology of Disease · doi:10.1016/j.nbd.2021.105398 · Cited by 28 · see citing works
Asparagine endopeptidase cleaves tau at N167 after uptake into microglia
Behrendt, A., Bichmann, M., Ercan-Herbst, E., Haberkant, P., Schöndorf, D. C., Wolf, M., Fahim, S. A., Murolo, E., & Ehrnhoefer, D. E. (2019) · Neurobiology of Disease · doi:10.1016/j.nbd.2019.104518 · Cited by 26 · see citing works
Chen, K., Li, F., Zhang, S., Chen, Y., Ikezu, T. C., Li, Z., Martens, Y. A., Qiao, W., Meneses, A. D., Zhu, Y., et al. (2025) · Journal of Neuroinflammation · doi:10.1186/s12974-025-03420-8 · Cited by 27 · see citing works
“Notably, two other studies found that complete deletion of the murine Trem2 gene does not significantly affect tau pathology in PS19 mice [26, 31].”
STING Deletion Protects Against Amyloid β‐induced Alzheimer's Disease Pathogenesis
Thanos, J. M., Campbell, O. C., Cowan, M. N., Bruch, K. R., Moore, K. A., Ennerfelt, H. E., Natale, N. R., Mangalmurti, A., Kerur, N., & Lukens, J. R. (2025) · Alzheimer's & Dementia · doi:10.1002/alz.70305 · Cited by 26 · see citing works
“57 The divergent roles that many discrete and hippocampal synaptic loss.”
Differential Roles of TREM2+ Microglia in Anterograde and Retrograde Axonal Injury Models
Manich, G., Gómez‐López, A. R., Almolda, B., Villacampa, N., Recasens, M., Shrivastava, K., González, B., & Castellano, B. (2020) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2020.567404 · Cited by 26 · see citing works
“…being coincident with the previous general in vivo data in chronic (Jay et al., 2017a; Sayed et al., 2018) and acute CNS inflammatory injuries (Saber et al., 2017; Scott-Hewitt et al., 2017; Wu et al., 2017), as well as in other axonal injury models (Kobayashi et al., 2016; Tay et al., 2018).”
ResultKnowledge gaps in Alzheimer's disease immune biomarker research
Morgan, D., & Mielke, M. M. (2021) · Alzheimer s & Dementia · doi:10.1002/alz.12342 · Cited by 25 · see citing works
Anand, C., Maia, P. D., Torok, J., Mezias, C., & Raj, A. (2022) · Scientific Reports · doi:10.1038/s41598-022-25131-3 · Cited by 25 · see citing works
Lin, C., Kong, Y., Chen, Q., Zeng, J., Pan, X., & Miao, J. (2024) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2024.1420731 · Cited by 25 · see citing works
Microglia in Alzheimer’s Disease
Süß, P., & Schlachetzki, J. C. M. (2020) · Current Alzheimer Research · doi:10.2174/1567205017666200212155234 · Cited by 26 · see citing works
TREM2 Agonism with a Monoclonal Antibody Attenuates Tau Pathology and Neurodegeneration
Fassler, M., Benaim, C., & George, J. (2023) · Cells · doi:10.3390/cells12111549 · Cited by 22 · see citing works
“In a later study using the same murine model, heterozygous expression but not full deletion of TREM2 was associated with an accelerated Tau pathology [13].”
BackgroundZhao, Y., Guo, Q., Tian, J., Liu, W., & Wang, X. (2024) · Ageing Research Reviews · doi:10.1016/j.arr.2024.102596 · Cited by 22 · see citing works
Pathways linking Alzheimer’s disease risk genes expressed highly in microglia
Hodges, A. K., Piers, T. M., Collier, D., Cousins, O., & Pocock, J. M. (2021) · Neuroimmunology and Neuroinflammation · doi:10.20517/2347-8659.2020.60 · Cited by 21 · see citing works
“In Tau-driven models, the picture is more complex with some studies showing loss of TREM2 to be protective in the presence of Tau pathology([124,125]) while others show it leads to worse outcomes([126,127]).”
APOEε4 and risk of Alzheimer’s disease – time to move forward
Lefterov, I. M., Fitz, N. F., Lü, Y., & Koldamova, R. P. (2023) · Frontiers in Neuroscience · doi:10.3389/fnins.2023.1195724 · Cited by 23 · see citing works
“In P301S tau mice expressing mouse Apoe the loss of Trem2 (Sayed et al., 2018; Leyns et al., 2019) or the expression of loss-of-function R47H variant (Gratuze et al.”
BackgroundCharacterization of gene expression profiles in the mouse brain after 35 days of spaceflight mission
Holley, J. M., Stanbouly, S., Pecaut, M. J., Willey, J. S., Delp, M. D., & Mao, X. W. (2022) · npj Microgravity · doi:10.1038/s41526-022-00217-4 · Cited by 21 · see citing works
The innate immune response in tauopathies
Johnson, A. M., & Lukens, J. R. (2023) · European Journal of Immunology · doi:10.1002/eji.202250266 · Cited by 20 · see citing works
Alzheimer’s Disease Genetics: A Dampened Microglial Response?
Chatila, Z. K., & Bradshaw, E. M. (2021) · The Neuroscientist · doi:10.1177/10738584211024531 · Cited by 20 · see citing works
Cholesterol Metabolism in CNS Diseases: The Potential of SREBP2 and LXR as Therapeutic Targets
Wang, N.-Q., Sun, P.-X., Shen, Q.-Q., & Deng, M.-Y. (2025) · Molecular Neurobiology · doi:10.1007/s12035-024-04672-w · Cited by 19 · see citing works
“Notably, studies have shown that TREM2 haploinsufficiency causes more severe impairments in microglial function and exacerbates tau pathology compared to complete TREM2 loss [114].”
TREM2-Deficient Microglia Attenuate Tau Spreading In Vivo
Lee-Gosselin, A., Jury-Garfe, N., You, Y., Dabin, L., Soni, D., Dutta, S., Rochet, J.-C., Kim, J., Oblak, A. L., & Lasagna-Reeves, C. A. (2023) · Cells · doi:10.3390/cells12121597 · Cited by 19 · see citing works
“total reduction enhanced tau phosphorylation and aggregation [18].”
BackgroundInfluentialAyyubova, G. (2023) · European Journal of Neuroscience · doi:10.1111/ejn.15914 · Cited by 20 · see citing works
“Some studies showed that loss of TREM2 is protective in the presence of tau pathology (Leyns et al., 2019), whereas others indicate that it is detrimental (Bemiller et al., 2017; Sayed et al., 2018).”
BackgroundMicroglia Biomarkers in Alzheimer’s Disease
Zhang, P., Hu, H., Tan, L., & Yu, J. (2021) · Molecular Neurobiology · doi:10.1007/s12035-021-02348-3 · Cited by 18 · see citing works
Deletion of Abi3/Gngt2 influences age-progressive amyloid β and tau pathologies in distinctive ways
Ibanez, K. R., McFarland, K. N., Phillips, J., Allen, M., Lessard, C. B., Zobel, L., De La Cruz, E. G., Shah, S., Vo, Q., Wang, X., et al. (2022) · Alzheimer's Research & Therapy · doi:10.1186/s13195-022-01044-1 · Cited by 18 · see citing works
Sánchez‐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
“Intriguingly, TREM2 haploinsufficiency, but not complete loss of TREM2, exacerbates tau pathology and impairs microglia response to injury in the transgenic PS19Tg mouse model primary tauopathy.(31) We show that TREM2 expression levels are augmented in a brain area affected by pathological p-tau deposits.”
BackgroundImmunological aspects of central neurodegeneration
Niso‐Santano, M., Fuentes, J. M., & Galluzzi, L. (2024) · Cell Discovery · doi:10.1038/s41421-024-00666-z · Cited by 16 · see citing works
“To add yet another layer of complexity, in at least some AD models, while Trem2 haploinsuf fi ciency appears to aggravate tau pathology in mice, complete Trem2 loss reportedly limits tau-driven microglial activation and atrophy 48 .”
- Authors
- Sayed, F. A., Telpoukhovskaia, M., Kodama, L., Li, Y., Zhou, Y., Le, D., Hauduc, A., Ludwig, C., Gao, F., Clelland, C., Zhan, L., Cooper, Y. A., Davalos, D., Akassoglou, K., Coppola, G., & Gan, L.
- Affiliations
- Gladstone Institutes (US)
- University of California, Los Angeles (US)
- Corresponding author
- Gan, Li
- ORCID
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2018-09-19
- Volume
- 115
- Issue
- 40
- Pages
- 10172-10177
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC6176614
- OpenAlex
- W2890556232
- Cited by
- 229
- References
- 35
- Citations by year
- 2026: 15 · 2025: 23 · 2024: 31 · 2023: 40 · 2022: 44 · 2021: 33 · 2020: 19 · 2019: 21 · 2018: 3
- FWCI
- 8.55
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion, cc-by-nc-nd)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- eScholarship (California Digital Library) (submittedVersion, cc-by-nc-nd)
- Funders
- HHS | NIH | National Institute on Aging (R01AG051390, R01AG054214)
- 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, tauopathy, microglial activation, TREM2 knockout mice, pro-inflammatory markers
- MeSH terms
- Aging, Alzheimer Disease, Animals, Membrane Glycoproteins, Receptors, Immunologic, Microglia, Mice, Knockout, Mutation, Missense, Mice, Haploinsufficiency, Hemizygote
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.
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