Microglia, Trem2, and Neurodegeneration
Open accessAbstract
Microglia are a specialized type of neuroimmune cells that undergo morphological and molecular changes through multiple signaling pathways in response to pathological protein aggregates, neuronal death, tissue injury, or infections. Microglia express Trem2, which serves as a receptor for a multitude of ligands enhancing their phagocytic activity. Trem2 has emerged as a critical modulator of microglial activity, especially in many neurodegenerative disorders. Human TREM2 mutations are associated with an increased risk of developing Alzheimer disease (AD) and other neurodegenerative diseases. Trem2 plays dual roles in neuroinflammation and more specifically in disease-associated microglia. Most recent developments on the molecular mechanisms of Trem2, emphasizing its role in uptake and clearance of amyloid β (Aβ) aggregates and other tissue debris to help protect and preserve the brain, are encouraging. Although Trem2 normally stimulates defense mechanisms, its dysregulation can intensify inflammation, which poses major therapeutic challenges. Recent therapeutic approaches targeting Trem2 via agonistic antibodies and gene therapy methodologies present possible avenues for reducing the burden of neurodegenerative diseases. This review highlights the promise of Trem2 as a therapeutic target, especially for Aβ-associated AD, and calls for more mechanistic investigations to understand the context-specific role of microglial Trem2 in developing effective therapies against neurodegenerative diseases.
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Inflammation, or neuroinflammation, is a crucial factor in the mechanisms behind AD.
“Inflammation, or neuroinflammation, is a crucial factor in the mechanisms behind AD.”
From Recent Advances in Therapeutics for the Treatment of Alzheimer’s Disease (2024) · cites this paper as [204]
In the healthy aging human brain, amyloid-β plaques have the ability to cause persistent inflammation in microglia.
“In the healthy aging human brain, amyloid-β plaques have the ability to cause persistent inflammation in microglia, which are the brain’s resident immune cells.”
From Recent Advances in Therapeutics for the Treatment of Alzheimer’s Disease (2024) · cites this paper as [204]
TREM2 agonists are being investigated as potential therapeutic agents because they reduce inflammation and encourage amyloid-beta microglial phagocytosis.
“TREM2 agonists are being investigated as potential therapeutic agents since they reduce inflammation and encourage amyloid-beta microglial phagocytosis [202,203,204,205].”
From Recent Advances in Therapeutics for the Treatment of Alzheimer’s Disease (2024) · cites this paper as [204]
TREM2 receptor interaction plays a key role in identifying microglia for the build-up of debris and damage during the regulation of microglial activation.
“TREM2 receptor interaction plays a key role in identifying microglia for the build-up of debris and damage during the regulation of microglial activation.”
From Recent Advances in Therapeutics for the Treatment of Alzheimer’s Disease (2024) · cites this paper as [204]
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“In 2013, two independent studies by Jonsson et al. (Jonsson and others 2013) and Guerreiro et al. (Guerreiro and Hardy 2013) identified a rare variant, R47H in human TREM2 gene, which significantly increased the risk of developing AD.”
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“Some studies have shown that Trem2 deficiency led to less microgliosis, astrogliosis, and expression of markers of DAMs and inflammation, leading to reduced hippocampal atrophy (Gratuze and others 2020).”
Clayton, K., Delpech, J. C., Herron, S., Iwahara, N., Ericsson, M., Saito, T., Saido, T. C., Ikezu, S., & Ikezu, T. (2021) · Molecular Neurodegeneration · doi:10.1186/s13024-021-00440-9 · Cited by 245 · cited 1× · see citing works
“…of a unique microglial subtype in neurodegenerative diseases, termed disease-associated microglia (DAM) (Deczkowska and others 2018) or microglial neurodegenerative (MGnD) phenotype (Clayton and others 2021; Krasemann and others 2017), has been a significant development in the microglia field.”
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 · cited 1× · see citing works
“This disease is known to be linked with specific mutations in the ectodomains of Trem2, namely, Y38C, W50C, T66M, and V126G (Guerreiro and others 2013a; Guerreiro and others 2013b; Kleinberger and others 2017; Le Ber and others 2014).”
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 · cited 2× · see citing works
“Trem2 also associates with anionic lipids, lipoproteins, and other polyvalent ligands (Belsare and others 2022; Ibach and others 2021; Kober and others 2016; Wang and others 2015).”
Baik, S. H., Kang, S., Son, S. M., & Mook-Jung, I. (2016) · Glia · doi:10.1002/glia.23074 · Cited by 234 · see citing works
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
Sayed, F. A., Telpoukhovskaia, M., Kodama, L., Li, Y., Zhou, Y., Le, D., Hauduc, A., Ludwig, C., Gao, F., Clelland, C., et al. (2018) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1811411115 · Cited by 229 · cited 1× · 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).”
Liu, 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
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 · cited 1× · see citing works
“The impaired phagocytic activity leads to plaque accumulation, triggering neuroinflammation and neuronal damage (Meilandt and others 2020).”
Fraser, D. A., Pisalyaput, K., & Tenner, A. J. (2009) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2009.06494.x · Cited by 196 · see citing works
TREM2 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
Morenas‐Rodríguez, E., Li, Y., Nuscher, B., Franzmeier, N., Xiong, C., Suárez‐Calvet, M., Fagan, A. M., Schultz, S., Gordon, B. A., Benzinger, T. L. S., et al. (2022) · The Lancet Neurology · doi:10.1016/s1474-4422(22)00027-8 · Cited by 177 · see citing works
TREM2 in CNS homeostasis and neurodegenerative disease
Painter, M. M., Atagi, Y., Liu, C.-C., Rademakers, R., Xu, H., Fryer, J. D., & Bu, G. (2015) · Molecular Neurodegeneration · doi:10.1186/s13024-015-0040-9 · Cited by 169 · see citing works
Zhong, L., Sheng, X., Wang, W., Li, Y., Zhuo, R., Wang, K., Zhang, L., Hu, D.-D., Hong, Y., Chen, L., et al. (2023) · Immunity · doi:10.1016/j.immuni.2023.06.016 · Cited by 168 · see citing works
TREM2 R47H Variant as a Risk Factor for Early-Onset Alzheimer's Disease
Pottier, C. P., collaborators, G., Wallon, D., Rousseau, S., Rovelet‐Lecrux, A., Richard, A., Rollin‐Sillaire, A., Frébourg, T., Campion, D., & Hannequin, D. (2013) · Journal of Alzheimer s Disease · doi:10.3233/jad-122311 · Cited by 162 · see citing works
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
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
Sayed, F. A., Kodama, L., Fan, L., Carling, G. K., Udeochu, J. C., Le, D., Li, Q., Zhou, L., Wong, M. Y., Horowitz, R., et al. (2021) · Science Translational Medicine · doi:10.1126/scitranslmed.abe3947 · Cited by 155 · see citing works
TREM2 modulates microglia phenotypes in the neuroinflammation of Parkinson's disease
Zhang, Y., Feng, S., Nie, K., Li, Y., Gao, Y., Gan, R., Wang, L., Li, B., Sun, X., Wang, L., et al. (2018) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2018.03.226 · Cited by 152 · 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
Price, B. R., Sudduth, T. L., Weekman, E. M., Johnson, S. N., Hawthorne, D., Woolums, A. E., & Wilcock, D. M. (2020) · Journal of Neuroinflammation · doi:10.1186/s12974-020-01915-0 · Cited by 143 · cited 2× · see citing works
“In line with this finding, other studies have shown that two monoclonal antibodies, AL002c and AL002a (Price and others 2020; Wang and others 2020), tailored for human and mouse Trem2, respectively, have been confirmed to ameliorate A β pathology in vivo, supporting the therapeutic potential of targeting Trem2.”
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 · cited 1× · see citing works
“Current evidence indicates that the presence of the T66M variant in individuals is associated with significantly reduced concentrations of soluble Trem2 (sTrem2) in the cerebrospinal fluid (Henjum and others 2016; Heslegrave and others 2016; Piccio and others 2016).”
Shi, Q., Chang, C., Saliba, A., & Bhat, M. A. (2022) · Journal of Neuroscience · doi:10.1523/jneurosci.2427-21.2022 · Cited by 134 · see citing works
Self-citationSchlepckow, 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
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
Ren, M., Guo, Y., Wei, X., Yan, S., Qin, Y., Zhang, X., Jiang, F., & Lou, H. (2018) · Experimental Neurology · doi:10.1016/j.expneurol.2018.01.016 · Cited by 118 · cited 1× · see citing works
“Furthermore, there is evidence that overexpression of Trem2 attenuates neuroinflammation and offers protection to dopaminergic neurons in experimental models of PD (Ren and others 2018).”
Aminophospholipids are signal-transducing TREM2 ligands on apoptotic cells
Shirotani, K., Hori, Y., Yoshizaki, R., Higuchi, E., Colonna, M., Saito, T., Hashimoto, S., Saito, T., Saido, T. C., & Iwata, N. (2019) · Scientific Reports · doi:10.1038/s41598-019-43535-6 · Cited by 116 · see citing works
Huang, P., Zhang, Z., Zhang, P., Feng, J., Xie, J., Zheng, Y., Liang, X., Zhu, B., Chen, Z., Feng, S., et al. (2024) · Molecular Neurobiology · doi:10.1007/s12035-023-03713-0 · Cited by 111 · 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
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
Guo, Y., Wei, X., Yan, H., Qin, Y., Yan, S., Liu, J., Zhao, Y., Jiang, F., & Lou, H. (2019) · The FASEB Journal · doi:10.1096/fj.201900992r · Cited by 101 · cited 1× · see citing works
“In patients with PD, TREM2 expression is up-regulated in microglia around the α -synuclein deposits (Guo and others 2019; Zhang and others 2018).”
Rapamycin and Alzheimer disease: a double-edged sword?
Carosi, J. M., & Sargeant, T. J. (2019) · Autophagy · doi:10.1080/15548627.2019.1615823 · Cited by 99 · cited 2× · see citing works
“Addressing the lysosomal dysfunction in microglia, through mechanisms dependent on or independent of mTOR, can ameliorate issues related to lysosomal, lipid, and activation states that arise due to TREM2 mutations (Carosi and Sargeant 2019).”
Homozygous TREM2 mutation in a family with atypical frontotemporal dementia
Ber, I. L., de Septenville, A. D., Guerreiro, R., Bras, J., Camuzat, A., Caroppo, P., Lattante, S., Couarch, P., Kabashi, E., Bouya-Ahmed, K., et al. (2014) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2014.04.010 · Cited by 98 · see citing works
Tagliatti, E., Desiato, G., Mancinelli, S., Bizzotto, M., Gagliani, M. C., Faggiani, E., Hernández‐Soto, R., Cugurra, A., Poliseno, P., Miotto, M., et al. (2023) · Immunity · doi:10.1016/j.immuni.2023.12.002 · Cited by 89 · see citing works
TREM2-Dependent Effects on Microglia in Alzheimer’s Disease
Zhou, Y., Ulland, T. K., & Colonna, M. (2018) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2018.00202 · Cited by 88 · see citing works
TREM2 Variants and Neurodegenerative Diseases: A Systematic Review and Meta-Analysis
Zhou, S.-L., Tan, C., Hou, X., Cao, X., Tan, L., & Yu, J. (2019) · Journal of Alzheimer s Disease · doi:10.3233/jad-181038 · Cited by 70 · 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 · cited 1× · see citing works
“In addition, Trem2 influences the bioenergetics of neurons (Tagliatti and others 2024), and in the context of AD, impaired Trem2 function could affect neuronal energy metabolism, exacerbating the energy deficits commonly observed in AD brains (Qu and Li 2020).”
Wu, M., Liao, M., Huang, R., Chen, C., Tian, T., Wang, H., Li, J., Li, J., Sun, Y., Wu, C., et al. (2020) · Genes & Diseases · doi:10.1016/j.gendis.2020.05.005 · Cited by 69 · cited 1× · see citing works
“Alternatively, Wu et al. (Wu and others 2022) used an adeno-associated virus–mediated Trem2 overexpression in the hippocampus in a high-fat diet mouse model.”
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
Uncovering Disease Mechanisms in a Novel Mouse Model Expressing Humanized APOEε4 and Trem2*R47H
Kotredes, K. P., Oblak, A., Pandey, R. S., Lin, P. B.-C., Garceau, D., Williams, H., Uyar, A., O’Rourke, R., O’Rourke, S., Ingraham, C., et al. (2021) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2021.735524 · Cited by 66 · see citing works
Jairaman, A., McQuade, A., Granzotto, A., Kang, Y. J., Chadarevian, J. P., Gandhi, S., Parker, I., Smith, I., Cho, H., Sensi, S. L., et al. (2022) · eLife · doi:10.7554/elife.73021 · Cited by 61 · cited 1× · see citing works
“Elevated calcium levels, along with DAG, activate protein kinase C (PKC) and other kinases, facilitating actin cytoskeletal rearrangements essential for phagocytic cup formation and engulfment of targets (Jairaman and others 2022).”
Wangler, L. M., & Godbout, J. P. (2023) · Trends in Neurosciences · doi:10.1016/j.tins.2023.08.008 · Cited by 59 · cited 1× · see citing works
“The activation of microglia occurs via several signaling pathways that include the nuclear factor (NF)– κ B pathway, inflammasomes, and various receptor-mediated pathways (Wangler and Godbout 2023), which help regulate the production of cytokines, chemokines, and other cell signaling mediators.”
Biel, D., Suárez‐Calvet, M., Hager, P., Rubinski, A., Dewenter, A., Steward, A., Roemer, S. N., Ewers, M., Haass, C., Brendel, M., et al. (2023) · EMBO Molecular Medicine · doi:10.15252/emmm.202216987 · Cited by 55 · see citing works
Wang, P., Yang, P., Qian, K., Li, Y., Xu, S., Meng, R., Guo, Q., Cheng, Y., Cao, J., Xu, M., et al. (2021) · Biomaterials · doi:10.1016/j.biomaterials.2021.121360 · Cited by 54 · 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
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
Profiling TREM2 expression in amyotrophic lateral sclerosis
Jericó, I., Vicuña‐Urriza, J., Blanco‐Luquin, I., Macías, M., Martínez‐Merino, L., Roldán, M., Rojas‐García, R., Pagola, I., Carbayo, Á., de Luna, N., et al. (2023) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2023.01.013 · Cited by 40 · cited 1× · see citing works
“In ALS, a disease characterized by degenerating motor neurons, Trem2 expression is significantly altered in microglia (Jerico and others 2023; Xie and others 2022b).”
Liu, S., Cao, X., Wu, Z., Deng, S., Fu, H., Wang, Y., & Liu, F. (2022) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2022.967825 · Cited by 37 · see citing works
Targeting TREM2 for Parkinson’s Disease: Where to Go?
Li, X., & Zhang, F. (2021) · Frontiers in Immunology · doi:10.3389/fimmu.2021.795036 · Cited by 36 · cited 1× · see citing works
“Recent studies have begun to unravel the role of Trem2 in PD (Li and Zhang 2021).”
Microglial TREM2 in amyotrophic lateral sclerosis
Xie, M., Zhao, S., Bosco, D. B., Nguyen, A. T., & Wu, L. (2021) · Developmental Neurobiology · doi:10.1002/dneu.22864 · Cited by 34 · see citing works
Variant TREM2 Signaling in Alzheimer's Disease
Olufunmilayo, E. O., & Holsinger, R. M. D. (2022) · Journal of Molecular Biology · doi:10.1016/j.jmb.2022.167470 · Cited by 32 · cited 1× · see citing works
“Trem2 engages in signaling pathways that are crucial for microglial activation, survival, and phagocytic functions (Olufunmilayo and Holsinger 2022).”
Ibach, M., Mathews, M., Linnartz‐Gerlach, B., Theil, S., Kumar, S., Feederle, R., Brüstle, O., Neumann, H., & Walter, J. (2020) · Glia · doi:10.1002/glia.23953 · Cited by 24 · cited 2× · see citing works
“Trem2 also associates with anionic lipids, lipoproteins, and other polyvalent ligands (Belsare and others 2022; Ibach and others 2021; Kober and others 2016; Wang and others 2015).”
Dardiotis, E., Rikos, D., Siokas, V., Aloizou, A., Tsouris, Z., Sakalakis, E., Brotis, A. G., Bogdanos, D. P., & Hadjigeorgiou, G. M. (2020) · International Journal of Neuroscience · doi:10.1080/00207454.2020.1750388 · Cited by 23 · see citing works
Peripheral sTREM2-Related Inflammatory Activity Alterations in Early-Stage Alzheimer’s Disease
Weber, G. E., Khrestian, M., Tuason, E. D., Shao, Y. Y., Pillai, J. A., Rao, S. M., Feng, H., Zhou, Y., Cheng, F., DeSilva, T. M., et al. (2022) · The Journal of Immunology · doi:10.4049/jimmunol.2100771 · Cited by 21 · see citing works
A 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.2023.08.011 · Cited by 15 · see citing works
MEK1/2 activity modulates TREM2 cell surface recruitment
Schapansky, J., Grinberg, Y. Y., Osiecki, D. M., Freeman, E. A., Walker, S. G., Karran, E. H., Gopalakrishnan, S. M., & Talanian, R. V. (2020) · Journal of Biological Chemistry · doi:10.1074/jbc.ra120.014352 · Cited by 14 · cited 1× · see citing works
“It was recently reported that inhibitors of MEK1/2 kinases significantly increase cell surface Trem2 protein expression, suggesting a new or indirect pathway for Trem2 regulation (Schapansky and others 2021).”
TREM2 as an evolving therapeutic target in Alzheimer’s disease
George, J. (2023) · Neural Regeneration Research · doi:10.4103/1673-5374.371360 · Cited by 14 · cited 2× · see citing works
“Such diverse functions place Trem2 at the forefront of neuroprotective mechanisms, making it a key target for potential therapeutic strategies (George 2023).”
Chen, X., Chen, Y., Wei, Q., Guo, X., Cao, B., Ru⁃wei, O., Zhao, B., & Shang, H. (2015) · Journal of the Neurological Sciences · doi:10.1016/j.jns.2015.05.010 · Cited by 13 · see citing works
Lack of association between TREM2 rs75932628 variant and amyotrophic lateral sclerosis
Siokas, V., Aloizou, A., Liampas, I., Tsouris, Z., Mentis, A. A., Nasios, G., Papadimitriou, D. A., Bogdanos, D. P., Hadjigeorgiou, G. M., & Dardiotis, E. (2021) · Molecular Biology Reports · doi:10.1007/s11033-021-06312-1 · Cited by 13 · see citing works
TREM2 activation promotes remyelination
Wood, H. B. (2020) · Nature Reviews Neurology · doi:10.1038/s41582-020-0404-9 · Cited by 8 · cited 1× · see citing works
“Trem2 activation has also been linked to promoting remyelination, further underscoring its role in debris clearance and recovery processes in CNS myelination (Wood 2020).”
Trem2 Enhances Demyelination in the Csf1r+/− Mouse Model of Leukoencephalopathy
Biundo, F., Chiţu, V., Gökhan, Ş., Chen, E., Oppong‐Asare, J., & Stanley, E. R. (2023) · Biomedicines · doi:10.3390/biomedicines11082094 · Cited by 8 · see citing works
Soluble TREM2 in body fluid in Alzheimer’s disease and Parkinson’s disease
Gu, L., Shu, H., & Wang, Y. (2023) · Neurological Sciences · doi:10.1007/s10072-023-06729-5 · Cited by 7 · see citing works
Rikos, D., Siokas, V., Mentis, A. A., Aloizou, A., Liampas, I., Tsouris, Z., Peristeri, E., Stamati, P., Hadjigeorgiou, G. M., & Dardiotis, E. (2022) · International Journal of Neuroscience · doi:10.1080/00207454.2022.2150844 · Cited by 5 · see citing works
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Neurovascular unit, neuroinflammation and neurodegeneration markers in brain disorders
Kempuraj, D., Dourvetakis, K. D., Cohen, J., Valladares, D. S., Joshi, R. S., Kothuru, S. P., Anderson, T., Chinnappan, B., Cheema, A. K., Klimas, N. G., et al. (2024) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2024.1491952 · Cited by 75 · see citing works
Recent Advances in Therapeutics for the Treatment of Alzheimer’s Disease
Thawabteh, A. M., Ghanem, A. W., AbuMadi, S., Thaher, D., Jaghama, W., Karaman, D., & Karaman, R. (2024) · Molecules · doi:10.3390/molecules29215131 · Cited by 56 · see citing works
Microglia-mediated neuroinflammation in traumatic brain injury: a review
Obukohwo, O. M., Oreoluwa, O. A., Andrew, U. O., & Williams, U. E. (2024) · Molecular Biology Reports · doi:10.1007/s11033-024-09995-4 · Cited by 47 · see citing works
Fołta, J., Rzepka, Z., & Wrześniok, D. M. (2025) · International Journal of Molecular Sciences · doi:10.3390/ijms26115177 · Cited by 47 · see citing works
“However, its dysregulation can exacerbate neuroinflammation, which poses a challenge for future possible therapeutic strategies [93,102,103].”
Mitochondrial DAMPs: Key mediators in neuroinflammation and neurodegenerative disease pathogenesis
Yu, H., Ren, K., Jin, Y., Zhang, L., Liu, H., Huang, Z., Zhang, Z., Chen, X., Yang, Y., & Wei, Z. (2024) · Neuropharmacology · doi:10.1016/j.neuropharm.2024.110217 · Cited by 44 · see citing works
Greven, J. A., Wydra, J. R., Greer, R. A., Zhi, C., Price, D. A., Svoboda, J. D., Camitta, C., Washington, M., Leung, D. W., Song, Y., et al. (2025) · Molecular Neurodegeneration · doi:10.1186/s13024-024-00795-9 · Cited by 39 · see citing works
“This signaling can enhance protective functions of microglia, including chemotaxis, phagocytosis, suppression of inflammatory signaling, and boosting microglia survival and proliferation [5].”
He, C., Chen, B., Yang, H., & Zhou, X. (2025) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2025.1554398 · Cited by 38 · see citing works
Microglial dysfunction in Alzheimer's disease: Mechanisms, emerging therapies, and future directions
Azmal, M., Paul, J. K., Prima, F. S., Haque, A. N. M. S. N. B., Meem, M., & Ghosh, A. (2025) · Experimental Neurology · doi:10.1016/j.expneurol.2025.115374 · Cited by 28 · see citing works
Advancements and challenges in mouse models of Alzheimer’s disease
Qian, Z., Li, Y., & Ye, K. (2024) · Trends in Molecular Medicine · doi:10.1016/j.molmed.2024.10.010 · Cited by 28 · see citing works
Kalkman, H. O., & Smigielski, L. (2025) · Molecular Neurobiology · doi:10.1007/s12035-025-04989-0 · Cited by 29 · see citing works
TREM2 in Neurodegenerative Disorders: Mutation Spectrum, Pathophysiology, and Therapeutic Targeting
Yang, H.-W., Kim, D., Yang, Y., Bagyinszky, E., & An, S. S. A. (2025) · International Journal of Molecular Sciences · doi:10.3390/ijms26157057 · Cited by 25 · see citing works
“Because TREM2 was suggested to play a crucial role in maintaining brain homeostasis, these Thr66Met-induced disturbances hinder its function, potentially compromising microglial viability and activity [144,145].”
Protective genetic variants against Alzheimer's disease
Mariño, C., Malotaux, V., Giudicessi, A., Aguillon, D. F., Falla, D. S., Lopera, F. J., & Quiroz, Y. T. (2025) · The Lancet Neurology · doi:10.1016/s1474-4422(25)00116-4 · Cited by 20 · see citing works
Peng, X., Guo, H.-S., Zhang, X., Wu, X., Ruganzu, J. B., Wu, S., Zhao, M.-T., Li, L., Yang, Y., Ji, S., et al. (2025) · Experimental Neurology · doi:10.1016/j.expneurol.2025.115205 · Cited by 17 · see citing works
TREM2 as a regulator of obesity-induced cardiac remodeling: mechanisms and therapeutic insights
Chung, E., Zhang, D., Porras, M. G., & Hsu, C. G. (2025) · American Journal of Physiology-Heart and Circulatory Physiology · doi:10.1152/ajpheart.00075.2025 · Cited by 16 · see citing works
Kaur, R., Kumar, S., & Singh, L. (2025) · Cytokine · doi:10.1016/j.cyto.2025.156974 · Cited by 16 · see citing works
Seo, D., Choi, Y., Jeong, E., Bang, S., Lee, J. S., Jang, I.-H., Choi, L., Kim, J. H., Shin, W., Seo, B.-R., et al. (2025) · Nature Communications · doi:10.1038/s41467-025-65597-z · Cited by 15 · see citing works
Njoku, G. C., & Kanmogne, G. D. (2025) · International Journal of Molecular Sciences · doi:10.3390/ijms26189069 · Cited by 15 · see citing works
“Notably, multiple studies have demonstrated that TREM2 plays a role in AD pathogenesis by regulating microglial phagocytosis, inflammatory response, proliferation, and lipid metabolism [40,111,112,121–124].”
Peng, X., Yang, Z.-K., Guo, H., Wu, X., Ruganzu, J. B., Liu, Z.-Z., Wu, S.-D., & Yang, W.-N. (2025) · Molecular Neurobiology · doi:10.1007/s12035-025-05449-5 · Cited by 11 · see citing works
“…with the DNAX-activating protein of 12 kDa (DAP12) to form a receptor complex that subsequently leads to the activation of downstream signaling cascades, such as phosphatidylinositol 3-kinase/protein kinase B (PI3K/ Akt) and extracellular signal-regulated protein kinase 1 and 2 (ERK1/2) [12, 13].”
Shifting Microglial Phenotypes: Targeting Disease-Associated Microglia in Neurodegeneration
Sasidharan, A., Somayaji, Y., & Fernandes, R. (2025) · ACS Chemical Neuroscience · doi:10.1021/acschemneuro.5c00159 · Cited by 10 · see citing works
Systems biology of Alzheimer’s Disease: a scoping review of key pathways and mechanisms
Bice, P. J., Nho, K. T., Ertekin‐Taner, N., & Saykin, A. J. (2026) · Molecular Neurodegeneration · doi:10.1186/s13024-026-00934-4 · Cited by 13 · see citing works
El-Hamri, M.-A., & Abboussi, O. (2026) · Ageing Research Reviews · doi:10.1016/j.arr.2026.103138 · Cited by 9 · see citing works
Targeting Microglial Activation to Modulate Neuroinflammation in Alzheimer’s Disease
Patil, V., Sharma, A., Parekh, B. K., Farah, H., Jyothi, S. R., Mishra, S. S., Nanda, A., Al-Hasnaawei, S., & Mishra, M. K. (2025) · NeuroMolecular Medicine · doi:10.1007/s12017-025-08898-2 · Cited by 9 · see citing works
Wang, Y., Wang, Z., Hao, H., Zhao, Y., Wang, J., & Wang, W. (2025) · Toxics · doi:10.3390/toxics13010037 · Cited by 7 · see citing works
“TREM2 can regulate proinflammatory and anti-inflammatory responses, cytophagocytosis, energy metabolism, and so on [10].”
Sharma, A., & Singh, T. G. (2025) · Brain Research · doi:10.1016/j.brainres.2025.150047 · Cited by 6 · see citing works
Liu, W., Liu, Y., Guo, X., Cao, C., Weng, S., & Peng, D. (2026) · International Immunopharmacology · doi:10.1016/j.intimp.2026.116167 · Cited by 5 · see citing works
TREM2 and Pain Development: An Old Molecule, a New Target
Fan, Z., Huang, C., Li, X., Pan, R., Cai, H., Zhai, X., Ge, Z., & Sun, S. (2025) · Journal of Neurochemistry · doi:10.1111/jnc.70188 · Cited by 3 · see citing works
Sardari, M., Sahafi, O. H., & Rezayof, A. (2025) · Brain Research · doi:10.1016/j.brainres.2025.150040 · Cited by 3 · see citing works
Wu, Y., Sun, Y., Chen, J., Hu, M., Zhang, X., Xiong, X., Yu, Z., Yang, X., Li, H., & Wang, Y. (2026) · Bioactive Materials · doi:10.1016/j.bioactmat.2026.02.056 · Cited by 3 · see citing works
Lai, L., Tang, Y., Song, G., Long, Y., Chen, C., Chen, C., & Li, W. (2026) · Acta Neurologica Belgica · doi:10.1007/s13760-026-03064-2 · Cited by 3 · see citing works
The Double Face of Microglia in the Brain
Rubio-Osornio, M., Rubio, C., Ganado, M., & Romo-Parra, H. (2026) · Neuroglia · doi:10.3390/neuroglia7010003 · Cited by 2 · see citing works
“In addition to immunological defense, microglia regulate processes like synaptic pruning, neurogenesis, apoptosis modulation, and redox equilibrium, establishing their crucial role in neural development and neurodegenerative disorders [5–8].”
McDaid, G., Vanek, J., Cromer, B. A., & Sümer, H. (2025) · Biomedicines · doi:10.3390/biomedicines13112783 · Cited by 2 · see citing works
“The TREM2 receptor in microglia has been highlighted as a key modulator of neuroinflammatory responses in AD [56], suggesting that targeting this pathway could afford therapeutic benefits.”
Nikanfar, M., Yousefi, H., & Nourazarian, A. (2026) · Molecular Neurobiology · doi:10.1007/s12035-026-05697-z · Cited by 2 · see citing works
“TREM2 is an innate immune receptor primarily found on microglial cells and macrophages in the central nervous system (CNS), where it plays a key role in modulating microglial function and neuroinflammatory responses [14, 15].”
Agnello, L., Ciaccio, A. M., Ben, F. D., Gambino, C. M., Piccoli, T., Midiri, M., Scazzone, C., Masucci, A., Tamburello, M., & Ciaccio, M. (2026) · Journal of Clinical Laboratory Analysis · doi:10.1002/jcla.70217 · Cited by 2 · see citing works
de Souza, M. R. M., Lindner, M. R., Mladinich, M. C., Gorbunova, E. E., Kirillov, V., Byrne, A. G., Laird, A. Y., Finnerty, C. E., Ikeda, P., Vorkas, C. K., et al. (2026) · mBio · doi:10.1128/mbio.01294-26 · Cited by 2 · see citing works
Revisiting TREM2: from multi-omics signaling networks to clinical translation
Yang, J., Wan, D., Ren, L., Lv, Y., & Zhao, H. (2026) · Frontiers in Immunology · doi:10.3389/fimmu.2026.1782384 · Cited by 2 · see citing works
Abdelaziz, A. M., & Eladawy, R. M. (2026) · Biochemical Pharmacology · doi:10.1016/j.bcp.2026.118381 · Cited by 2 · see citing works
The role of autoantibodies in Alzheimer's disease: Pathogenetic connections or epiphenomena?
Chatanaka, M. K., Prassas, I., Masters, C. L., & Diamandis, E. P. (2025) · Alzheimer s & Dementia · doi:10.1002/alz.70484 · Cited by 1 · see citing works
“30,31 Furthermore, the brain’s immune system response, with part of it being the neuroinflammatory response, implicates the activation of microglia and astrocytes, which are specialized immune cells in the CNS. 28 Dysregulation of this immune response can contribute to the neuronal damage and the…”
Lunghi, G., Pedroli, C., Ciampa, M. G., Mauri, L., Rouvière, L., Henriques, A., Callizot, N., Savino, B., & Fazzari, M. (2025) · International Journal of Molecular Sciences · doi:10.3390/ijms26157634 · Cited by 1 · see citing works
“The current study supports a complementary mechanism, showing that OligoGM1 facilitated intracellular α Syn clearance, particularly in TREM2(+) microglia, which are known to coordinate phagocytic and metabolic responses to neuronal damage [30].”
Geng, X., Yang, H., Wang, Z., Chen, Z., Chen, J., & Yang, M. (2025) · Pathogens · doi:10.3390/pathogens14111105 · Cited by 1 · see citing works
“Interestingly, Trem2 is a critical anti-inflammatory regulator expressed on dM φ , and its dysregulation exacerbates inflammation [44].”
Neuroinflammation and Its Impact on Autophagy in Neurodegeneration
Bhattacharya, K., Chanu, N. R., Das, D., & Kumpakha, R. (2025) · Springer eBooks · doi:10.1007/978-981-95-3945-1_1 · Cited by 1 · see citing works
Harnessing the microbiome to regulate myeloid TREM2 expression and innate immune responses
Mihori, S., Nichols, F. C., Jellison, E. R., Blesso, C. N., Graziano, V. R., Rathinam, V. A. K., & Clark, R. B. (2026) · ImmunoHorizons · doi:10.1093/immhor/vlaf073 · Cited by 1 · see citing works
Unmasking the hidden catalyst: How infections trigger Alzheimer's disease
Fülöp, T., Cohen, A. A., Frost, E. H., Lévesque, S., Khalil, A., Rodrigues, S., Desroches, M., Alami, M., Berrougui, H., Ramassamy, C., et al. (2026) · Journal of Alzheimer s Disease · doi:10.1177/13872877251415571 · Cited by 1 · see citing works
“198,199 In addition, TREM2 plays a critical role in regulating in fl ammatory responses and various cell signaling pathways that in fl uence microglial immune and regulatory functions.”
Li, D., Zhang, Z., Lei, L. U., Liu, J., Cai, W., Hou, J., Lu, Y., & Yu, G. (2026) · Cellular Signalling · doi:10.1016/j.cellsig.2026.112689 · Cited by 4 · see citing works
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“S5g), consistent with previous studies [78, 79].”
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Decoding acute neuroinflammatory states from the 3D architecture of in vitro microgliaPreprint
Chatzimpinou, A., Huber, J., Podlipensky, X., Cairns, J. L., Erozan, A. S., Chen, J.-H., Loconte, V., Gros, M. A. L., Hopf, C., Larabell, C. A., et al. (2025) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.64898/2025.12.19.695376
Immunopathogenesis of neurosyphilis: clinical management perspectives
Bekhalo, V. A., & Loseva, O. K. (2025) · Russian Journal of Infection and Immunity · doi:10.15789/2220-7619-ion-18030
Zafar, S., Rasheed, U., & Zerr, I. (2026) · IntechOpen eBooks · doi:10.5772/intechopen.1013648
Kiriyama, Y., Nakatsuma, A., Tokumaru, H., Sadamoto, H., & Nochi, H. (2026) · Metabolites · doi:10.3390/metabo16030189
“Microglia detect and phagocytose surrounding APOE particles and denatured myelin lipids via the triggering receptor expressed on myeloid cells 2, thereby preventing neuroinflammation caused by excessive lipid accumulation [34,35].”
Is Alzheimer’s an Autoimmune Disease?
Corrada, B. R., & Speth, R. C. (2026) · Molecular Neurobiology · doi:10.1007/s12035-026-05790-3
Liu, W., Bai, Y., Qu, W., Zhang, X., Zhou, S., Luo, H., Zhu, M., Li, D., & Fang, X. (2026) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2026.1752446
“Research indicates that TREM2, upon binding A β , modulates microglial inflammatory responses, migration, and phagocytic clearance of A β deposits (Liu et al., 2020; Shi et al., 2025; Wei et al., 2024).”
Microglia and Astrocytes in the Lateral Vestibular Nuclei of Mice after Vestibular Stimulation
Mikheeva, I., Zhuikova, N., Fedorov, D., Antonova, O., Pavlik, L., & Arkhipov, V. (2026) · Acta Naturae · doi:10.32607/actanaturae.27673 · Cited by 1 · see citing works
“Microglial activation is observed in patients with Parkinson’s disease, Alzheimer’s disease, multiple sclerosis, and other neurodegenerative disorders [11].”
Saed, A., Akbarzadeh, M., Gohari, F., Asadrouh, N., Jahromizadeh, A. M., Sabaie, H., Zarkesh, M., Hedayati, M., Azizi, F., & Daneshpour, M. (2026) · Human Genomics · doi:10.1186/s40246-026-00972-5
“…in microglial state-transition programs and neuroinflammatory responses (including the TREM2 - APOE axis), which influence responses to injury and metabolic stress, offering a plausible neurobiological rationale for delirium vulnerability, even though the shared variants differ [27, 28].”
Tan, M., Zeng, J., Zhou, H., Yang, S., Wang, T., Zhong, M., 王彤宇, Liu, Z., Dai, Y., & Song, S. (2026) · Frontiers in Bioinformatics · doi:10.3389/fbinf.2026.1829278
Microglial activation and neuroinflammation: implications for neuropsychiatric symptoms
Uddin, T., Halder, C., Asma, A., Zaheen, A., Nahian, A., Nipun, R. S., Ferdous, J., Sarker, R., Misha, M. M., Tasnim, S., et al. (2026) · Exploration of Neuroprotective Therapy · doi:10.37349/ent.2026.1004158
Xu, Y., Zhang, G., Cui, X., & Sun, L. (2026) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2026.1838634
“Experimental studies consistently show that limiting maladaptive microglial activation reduces neuroinflammation, promotes A β clearance, and ameliorates cognitive and sensory dysfunction (Han et al., 2022; Shi et al., 2025; Zhou et al., 2024; Jia et al., 2025).”
Clinical Indication of the Role of Inflammation in Alzheimer’s Disease
Kumar, A., Sarkar, N., Kundu, M., Singh, V., & Dasgupta, D. (2026) · BENTHAM SCIENCE PUBLISHERS eBooks · doi:10.2174/9798898815646126010010
Wang, H., Wen, R., Parker, E., & Yang, L. (2026) · Cell Communication and Signaling · doi:10.1186/s12964-026-03083-9 · Cited by 2 · see citing works
“Therefore, the key to understanding TREM2 lies not in defining it as universally beneficial or harmful, but in precisely identifying the specific stages, pathological contexts, and cellular compartments where it retains a net protective function [66].”
Cellular state transitions in neuroimmune disorders
Naffaa, M. M. (2026) · Exploration of Immunology · doi:10.37349/ei.2026.1003261
Thakur, A., Sharma, R. R., Kumari, S., Prakash, D., & Devi, A. S. (2026) · Inflammopharmacology · doi:10.1007/s10787-026-02371-7
Wu, Y., Duan, L., Zhang, L., Wang, S., Yan, H., He, M., Wang, T., Li, L., & Gao, Y. (2026) · Frontiers in Immunology · doi:10.3389/fimmu.2026.1912989
“Whereas acute in fl ammatory stimulation often reduces TREM2 expression in cultured cells, increased TREM2 levels are frequently detected in diseased brain tissues (72).”
Shi, Y., Lin, J., Wu, Y., Xu, S., Zhang, N., Pan, Y., Ren, A., Fang, Y., Huang, Y., Zhang, X., et al. (2026) · iMeta · doi:10.1002/imt2.70163 · Cited by 1 · see citing works
“Shi et al. also reported that Trem2 had dual roles in neuroinflammation, supporting amyloid ‐ β clearance and tissue protection under normal conditions but driving inflammatory pathology when dysregulated [50].”
Clusterin as a therapeutic agent: Bridging the gap in brain and eye research
Zaman, B., Soundararajan, A., Pattabiraman, P. P., & Fouda, A. Y. (2026) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2026.109108
Gut Microbiota and Brain Aging: Identifying Keystone Biomarkers for Cognitive Health
Bhatia, M., Mishra, S. P., Mishra, R. K., Jain, S., Yadav, H., & Tomar, R. S. (2026) · Biomedicines · doi:10.3390/biomedicines14091975
“TREM2, an activator of innate immunity, is another genetic marker of AD, where a deficiency of which leads to a dysfunctional immune response and higher dementia risk [75].”
TREM2-directed therapy in Alzheimer’s disease: from therapeutic window to clinical translation
Kuang, Q., Li, S., Huang, W., Kuang, N., Liu, T., Huang, N., Luo, Y., & Huang, J. (2026) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2026.1938062
“…immune-related targets, triggering receptor expressed on myeloid cells 2 (TREM2) has attracted particular attention because it is supported simultaneously by human genetics, microglial biology, and expanding therapeutic development (Hashioka et al., 2020; Serradas et al., 2024; Shi et al., 2025).”
Tang, Y. M., Lo, R., Thiry, L., Fiorini, M. R., Farhan, S., Pandolfo, M., & Stifani, S. (2026) · Research Square · doi:10.21203/rs.3.rs-11037120/v1
Pascu, A., Ianole, V., & Danciu, M. (2026) · International Journal of Molecular Sciences · doi:10.3390/ijms27209346
“Initially characterized for its role in metabolism and phagocytosis, studied frequently in neuropathology [147], and reported to have anti-inflammatory roles in non-alcoholic liver steatosis [148], triggering receptor expressed on myeloid cells 2 (TREM2)—a type I transmembrane immunoglobulin…”
- Authors
- Shi, Q., Gutierrez, R. A., & Bhat, M. A.
- Affiliations
- The University of Texas at San Antonio Health Science Center (US)
- Corresponding author
- Bhat, Manzoor A.
- Venue
- The Neuroscientist
- Publisher
- SAGE Publications
- Published
- 2024-05-20
- Volume
- 31
- Issue
- 2
- Pages
- 159-176
- ISSN
- 1073-8584 (ISSN-L)
- 1089-4098
- PMC
- PMC11576490
- OpenAlex
- W4398172927
- Cited by
- 69
- References
- 121
- Citations by year
- 2026: 35 · 2025: 28 · 2024: 6
- FWCI
- 3.52
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- The Neuroscientist (publishedVersion, cc-by-nc)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc)
- PubMed Central (publishedVersion, cc-by-nc)
- PubMed (publishedVersion)
- Funders
- National Institute of General Medical Sciences (GM063074)
- Topics
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Immunology and Microbiology › Immunology › Phagocytosis and Immune Regulation
- Keywords
- microglia, TREM2, neurodegeneration, Alzheimer's disease, amyloid-beta clearance, neuroinflammation, disease-associated microglia, agonistic antibodies, gene therapy, phagocytosis, neuroimmune signaling
- MeSH terms
- Alzheimer Disease, Animals, Humans, Membrane Glycoproteins, Receptors, Immunologic, Amyloid beta-Peptides, Microglia, Neurodegenerative Diseases
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