What happens to microglial TREM2 in Alzheimer’s disease: Immunoregulatory turned into immunopathogenic?

Lue, L.-F.; Schmitz, C.; Walker, D.G.

doi:10.1016/j.neuroscience.2014.09.050

Cited by 63Neuroinflammation and Neurodegeneration MechanismsAlzheimer's disease research and treatmentsPhagocytosis and Immune Regulation

What happens to microglial TREM2 in Alzheimer’s disease: Immunoregulatory turned into immunopathogenic?

Lue, L.-F., Schmitz, C., Walker, D.G.·2015·Neuroscience

DOI 10.1016/j.neuroscience.2014.09.050

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Abstract

Microglia play major roles in initiation, coordination and execution of innate immunity in the brain. In the adult brain, these include maintenance of homeostasis, neuron and tissue repair, and eliminating infectious agents, apoptotic cells, and misfolded proteins. Some of these activities are accompanied by inflammatory reactions; and others are performed with no inflammatory effects. Under normal conditions, triggering receptor expressed on myeloid cells 2 (TREM2) belongs to the second category. It pairs with the adaptor protein DNAX-activating protein of 12kDa (DAP12) to induce phagocytosis of apoptotic neurons without inflammatory responses, and to regulate Toll-like receptor-mediated inflammatory responses, and microglial activation. Although ligands for TREM2 are largely unknown, the mitochondrial heat shock protein 60, expressed on cell surface of apoptotic neurons, is a specific ligand that activates TREM2-mediated phagocytosis by microglia. TREM2 also phagocytoses amyloid beta peptide in cultured cells. Several TREM2 mutations have been identified recently that increase the risk of Alzheimer's disease, Frontotemporal dementia, Parkinson's disease, and amyotrophic lateral sclerosis. Some of these mutations cause impaired proteolysis of full-length TREM2 at the plasma membrane to different degrees. The defects in the intramembrane cleavage result in dysfunction of phagocytosis signaling. The association of TREM2 mutations with neurodegenerative disease also calls for the understanding of the biology and pathological role of non-mutated TREM2 on human brains and microglia. This review provides a summary of current literature in TREM2 and DAP12 from several aspects, and proposes a theory that loss of TREM2 functions might contribute to the immunopathogenic role of microglia in Alzheimer's disease.

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Persistent upregulation of TREM2 and PU.1 expression in 5xFAD mice may represent a defense response of the innate immune system to counterbalance amyloid plaque accumulation in the AD brain.
“The persistent upregulation of TREM2 and PU.1 expression in 5 × FAD mice may represent a defense response of the innate immune system to counterbalance amyloid plaque accumulation in the AD brain (Lue et al., 2015).”
From PU.1 dictates β-amyloid-induced TREM2 expression upregulation in microglia in a transgenic model of Alzheimer’s disease (2025) · cites this paper as Lue et al., 2015

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Hamerman, J. A., Ni, M., Killebrew, J. R., Chu, C., & Lowell, C. A. (2009) · Immunological Reviews · doi:10.1111/j.1600-065x.2009.00841.x · Cited by 128 · see citing works
Attenuated Inflammatory Response in Triggering Receptor Expressed on Myeloid Cells 2 (TREM2) Knock-Out Mice following Stroke
Sieber, M. W., Jaenisch, N., Brehm, M., Guenther, M., Linnartz‐Gerlach, B., Neumann, H., Witte, O. W., & Frahm, C. (2013) · PLoS ONE · doi:10.1371/journal.pone.0052982 · Cited by 128 · see citing works
Dap12 and Trem2, molecules involved in innate immunity and neurodegeneration, are co-expressed in the CNS
Kiialainen, A., Hovanes, K., Paloneva, J., Kopra, O., & Peltonen, L. (2005) · Neurobiology of Disease · doi:10.1016/j.nbd.2004.09.007 · Cited by 114 · see citing works
Heterogeneity of presenile dementia with bone cysts (Nasu–Hakola disease)
Kondo, T., Takahashi, K., Kohara, N., Takahashi, Y., Hayashi, S., Takahashi, H., Matsuo, H., Yamazaki, M., Inoue, K., Miyamoto, K., et al. (2002) · Neurology · doi:10.1212/wnl.59.7.1105 · Cited by 106 · see citing works
Developmental Regulation of TREM2 and DAP12 Expression in the Murine CNS: Implications for Nasu-Hakola Disease
Thrash, J. C., Torbett, B. E., & Carson, M. J. (2008) · Neurochemical Research · doi:10.1007/s11064-008-9657-1 · Cited by 103 · see citing works
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
Microglial Immunoreceptor Tyrosine-Based Activation and Inhibition Motif Signaling in Neuroinflammation
Linnartz, B., Wang, Y., & Neumann, H. (2010) · International Journal of Alzheimer's Disease · doi:10.4061/2010/587463 · Cited by 87 · see citing works
Trafficking, a key player in regulated intramembrane proteolysis
Sannerud, R., & Annaert, W. G. (2008) · Seminars in Cell and Developmental Biology · doi:10.1016/j.semcdb.2008.11.004 · Cited by 84 · see citing works
The innate immune system in Alzheimer's disease
Boutajangout, A., & Wisniewski, T. (2013) · International Journal of Cell Biology · doi:10.1155/2013/576383 · Cited by 69 · see citing works
Microglia and the control of autoreactive T cell responses
Melchior, B., Puntambekar, S. S., & Carson, M. J. (2006) · Neurochemistry International · doi:10.1016/j.neuint.2006.04.002 · Cited by 67 · see citing works
Induction of DAP12 phosphorylation, calcium mobilization, and cytokine secretion by Ly49H
Gosselin, P., Mason, L. H., Willette‐Brown, J., Ortaldo, J. R., McVicar, D. W., & Anderson, S. K. (1999) · Journal of Leukocyte Biology · doi:10.1002/jlb.66.1.165 · Cited by 63 · see citing works
Evidence of Trem2 Variant Associated with Triple Risk of Alzheimer’s Disease
Abduljaleel, Z., Al-Allaf, F. A., Khan, W., Athar, M., Shahzad, N., Taher, M. M., Elrobh, M., Alanazi, M. S., & El-Huneidi, W. (2014) · PLoS ONE · doi:10.1371/journal.pone.0092648 · Cited by 54 · see citing works
The Enigmatic Function of TREM-2 in Osteoclastogenesis
Colonna, M., Turnbull, I. R., & Klesney‐Tait, J. (2007) · Advances in experimental medicine and biology · doi:10.1007/978-0-387-72009-8_13 · Cited by 52 · see citing works
Triggering receptor expressed in myeloid cells 2 (TREM2) trafficking in microglial cells: Continuous shuttling to and from the plasma membrane regulated by cell stimulation
Prada, I., Naum-Onganı́a, G., Buonsanti, C., Panina‐Bordignon, P., & Meldolesi, J. (2006) · Neuroscience · doi:10.1016/j.neuroscience.2006.03.058 · Cited by 49 · see citing works
Differential Modulation of TREM2 Protein during Postnatal Brain Development in Mice
Chertoff, M., Shrivastava, K., González, B., Acarín, L., & Giménez‐Llort, L. (2013) · PLoS ONE · doi:10.1371/journal.pone.0072083 · Cited by 46 · see citing works
Alzheimer's disease risk alleles in TREM2 illuminate innate immunity in Alzheimer's disease
Golde, T. E., Streit, W. J., & Chakrabarty, P. (2013) · Alzheimer s Research & Therapy · doi:10.1186/alzrt178 · Cited by 38 · see citing works
The Linker for Activation of B Cells (LAB)/Non-T Cell Activation Linker (NTAL) Regulates Triggering Receptor Expressed on Myeloid Cells (TREM)-2 Signaling and Macrophage Inflammatory Responses Independently of the Linker for Activation of T Cells
Whittaker, G. C., Orr, S. J., Quigley, L., Hughes, L., Francischetti, I. M. B., Zhang, W., & McVicar, D. W. (2010) · Journal of Biological Chemistry · doi:10.1074/jbc.m109.038398 · Cited by 33 · see citing works
The evolving role of semaphorins and plexins in the immune system: Plexin-A1 regulation of dendritic cell function
O’Connor, B. P., & Ting, J. P. ‐. (2008) · Immunologic Research · doi:10.1007/s12026-008-8026-0 · Cited by 30 · see citing works
A novel compound heterozygous mutation in the DAP12 gene in a patient with Nasu-Hakola disease
Kuroda, R., Satoh, J., Yamamura, T., Anezaki, T., Terada, T., Yamazaki, K., Obi, T., & Mizoguchi, K. (2006) · Journal of the Neurological Sciences · doi:10.1016/j.jns.2006.09.019 · Cited by 13 · see citing works

Flagged first, then by citations

2 of the 89 references couldn’t be matched to a known paper.

Sorted by citations

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
Late 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
The contribution of neuroinflammation to amyloid toxicity in Alzheimer's disease
Minter, M. R., Taylor, J. M., & Crack, P. J. (2016) · Journal of Neurochemistry · doi:10.1111/jnc.13411 · Cited by 451 · see citing works
Genetic variations underlying Alzheimer's disease: evidence from genome-wide association studies and beyond
Cuyvers, E., & Sleegers, K. (2016) · The Lancet Neurology · doi:10.1016/s1474-4422(16)00127-7 · Cited by 284 · see citing works
The Pathophysiological Role of Microglia in Dynamic Surveillance, Phagocytosis and Structural Remodeling of the Developing CNS
Arcuri, C., Mecca, C., Bianchi, R., Giambanco, I., & Donato, R. (2017) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2017.00191 · Cited by 279 · see citing works
Microglia and Aging: The Role of the TREM2–DAP12 and CX3CL1-CX3CR1 Axes
Mecca, C., Giambanco, I., Donato, R., & Arcuri, C. (2018) · International Journal of Molecular Sciences · doi:10.3390/ijms19010318 · Cited by 259 · see citing works
TREM2 macrophages drive NK cell paucity and dysfunction in lung cancer
Park, M. D., Reyes-Torres, I., LeBerichel, J., Hamon, P., LaMarche, N. M., Hegde, S., Belabed, M., Troncoso, L., Grout, J. A., Magen, A., et al. (2023) · Nature Immunology · doi:10.1038/s41590-023-01475-4 · Cited by 251 · see citing works
Alzheimer’s Disease, Oligomers, and Inflammation
Forloni, G., & Balducci, C. (2018) · Journal of Alzheimer s Disease · doi:10.3233/jad-170819 · Cited by 192 · see citing works
ADAM17 is the main sheddase for the generation of human triggering receptor expressed in myeloid cells (hTREM2) ectodomain and cleaves TREM2 after Histidine 157
Feuerbach, D., Schindler, P. A., Barske, C., Joller, S., Beng-Louka, E., Worringer, K. A., Kommineni, S., Kaykas, A., Ho, D. J., Ye, C., et al. (2017) · Neuroscience Letters · doi:10.1016/j.neulet.2017.09.034 · Cited by 172 · see citing works
<scp>APOE</scp>‐modulated Aβ‐induced neuroinflammation in Alzheimer's disease: current landscape, novel data, and future perspective
Tai, L. M., Ghura, S., Koster, K. P., Liakaite, V., Maienschein‐Cline, M., Kanabar, P., Collins, N., Ben‐Aissa, M., Lei, A. Z., Bahroos, N., et al. (2015) · Journal of Neurochemistry · doi:10.1111/jnc.13072 · Cited by 165 · see citing works
Identification of novel CSF biomarkers for neurodegeneration and their validation by a high-throughput multiplexed targeted proteomic assay
Heywood, W., Galimberti, D., Bliss, E., Sirka, E., Paterson, R. W., Magdalinou, N. K., Carecchio, M., Reid, E. S., Heslegrave, A., Fenoglio, C., et al. (2015) · Molecular Neurodegeneration · doi:10.1186/s13024-015-0059-y · Cited by 159 · 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 upregulation correlates with 5-hydroxymethycytosine enrichment in Alzheimer’s disease hippocampus
Celarain, N., de Gordoa, J. S., Zelaya, M. V., Roldán, M., Larumbe, R., Pulido, L., Echávarri, C., & Mendióroz, M. (2016) · Clinical Epigenetics · doi:10.1186/s13148-016-0202-9 · 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
Could Alzheimer’s Disease Originate in the Periphery and If So How So?
Morris, G., Berk, M., Maes, M. H. J., & Puri, B. K. (2018) · Molecular Neurobiology · doi:10.1007/s12035-018-1092-y · Cited by 83 · see citing works
Early Life Stress and Epigenetics in Late-onset Alzheimer’s Dementia: A Systematic Review
Lemche, E. (2018) · Current Genomics · doi:10.2174/1389202919666171229145156 · Cited by 82 · see citing works
Rosuvastatin enhances anti-inflammatory and inhibits pro-inflammatory functions in cultured microglial cells
Kata, D., Földesi, I., Fehér, L. Z., Hackler, L., Puskás, L. G., & Gulya, K. (2015) · Neuroscience · doi:10.1016/j.neuroscience.2015.11.053 · Cited by 63 · see citing works
Novel targets in Alzheimer’s disease: A special focus on microglia
Balducci, C., & Forloni, G. (2018) · Pharmacological Research · doi:10.1016/j.phrs.2018.01.017 · Cited by 61 · see citing works
Emerging Role of miR-21-5p in Neuron–Glia Dysregulation and Exosome Transfer Using Multiple Models of Alzheimer’s Disease
Garcia, G., Pinto, S., Ferreira, S., Lopes, D., Serrador, M. J., Fernandes, A., Vaz, A. R., Mendonça, A. D., Edenhofer, F., Malm, T., et al. (2022) · Cells · doi:10.3390/cells11213377 · Cited by 55 · see citing works
“Conversely, TREM2 is an AD-associated risk gene coding a transmembrane protein that is highly expressed in microglia and known to regulate their function in neurodegeneration [104,108].”
Background
Changes in the expression of genes related to neuroinflammation over the course of sporadic Alzheimer’s disease progression: CX3CL1, TREM2, and PPARγ
Strobel, S., Grünblatt, E., Riederer, P., Heinsen, H., Arzberger, T., Al‐Sarraj, S., Troakes, C., Ferrer, I., & Monoranu, C. M. (2015) · Journal of Neural Transmission · doi:10.1007/s00702-015-1369-5 · Cited by 54 · see citing works
Synonymous variants in HTRA1 implicated in AMD susceptibility impair its capacity to regulate TGF-β signaling
Friedrich, U., Datta, S., Schubert, T. E. O., Plößl, K., Schneider, M., Graßmann, F., Fuchshofer, R., Tiefenbach, K., Längst, G., & Weber, B. H. F. (2015) · Human Molecular Genetics · doi:10.1093/hmg/ddv346 · Cited by 50 · see citing works
Two macrophages, osteoclasts and microglia: from development to pleiotropy
Lee, J., Lee, I., Iimura, T., & Kong, S. W. (2021) · Bone Research · doi:10.1038/s41413-020-00134-w · Cited by 46 · see citing works
Alzheimer’s Disease: From Genetic Variants to the Distinct Pathological Mechanisms
Sun, Q., Xie, N., Tang, B., Li, R., & Shen, Y. (2017) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2017.00319 · Cited by 46 · see citing works
Microglial overexpression of fALS-linked mutant SOD1 induces SOD1 processing impairment, activation and neurotoxicity and is counteracted by the autophagy inducer trehalose
Massenzio, F., Peña‐Altamira, E., Petralla, S., Virgili, M., Zuccheri, G., Miti, A., Polazzi, E., Mengoni, I., Piffaretti, D., & Monti, B. (2018) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2018.10.013 · Cited by 45 · see citing works
Functional involvement of γ-secretase in signaling of the triggering receptor expressed on myeloid cells-2 (TREM2)
Glebov, K., Wunderlich, P., Karaca, I., & Walter, J. (2016) · Journal of Neuroinflammation · doi:10.1186/s12974-016-0479-9 · Cited by 44 · see citing works
Neuroinflammation in Alzheimer's disease and beneficial action of luteolin
Delgado, A., Cholevas, C., & Theoharides, T. C. (2021) · BioFactors · doi:10.1002/biof.1714 · Cited by 46 · see citing works
Genetic underpinnings in Alzheimer’s disease – a review
Moustafa, A. A., Hassan, M., Hewedi, D. H., Hewedi, I. H., Garami, J. K., Alashwal, H., Zaki, N., Seo, S., Vassilis Cutsuridis, A., Angulo, S. L., et al. (2017) · Reviews in the Neurosciences · doi:10.1515/revneuro-2017-0036 · Cited by 37 · see citing works
Microglia in Neurodegenerative Events—An Initiator or a Significant Other?
Harry, G. J. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22115818 · Cited by 37 · see citing works
Variable expression of microglial DAP12 and TREM2 genes in Nasu-Hakola disease
Sasaki, A., Kakita, A., Yoshida, K., Konno, T., Ikeuchi, T., Hayashi, S., Matsuo, H., & Shioda, K. (2015) · Neurogenetics · doi:10.1007/s10048-015-0451-3 · Cited by 36 · see citing works
RNA-sequencing reveals transcriptional up-regulation of Trem2 in response to bexarotene treatment
Lefterov, I. M., Schug, J., Mounier, A., Nam, K. N., Fitz, N. F., & Koldamova, R. P. (2015) · Neurobiology of Disease · doi:10.1016/j.nbd.2015.05.019 · Cited by 36 · see citing works
New Insights into the Molecular Bases of Familial Alzheimer’s Disease
D’Argenio, V., & Sarnataro, D. (2020) · Journal of Personalized Medicine · doi:10.3390/jpm10020026 · Cited by 35 · see citing works
Molecular and Cellular Crosstalk between Bone and Brain: Accessing Bidirectional Neural and Musculoskeletal Signaling during Aging and Disease
Schurman, C. A., Burton, J. B., Rose, J., Ellerby, L., Alliston, T. N., & Schilling, B. (2023) · Journal of Bone Metabolism · doi:10.11005/jbm.2023.30.1.1 · Cited by 33 · see citing works
Elevated expression of the retrotransposon LINE-1 drives Alzheimer’s disease-associated microglial dysfunction
Roy, N., Haq, I., Ngo, J. C., Bennett, D. A., Teich, A. F., Jager, P. L. D., Olah, M., & Sher, F. (2024) · Acta Neuropathologica · doi:10.1007/s00401-024-02835-6 · Cited by 35 · see citing works
Heterozygote galactocerebrosidase (GALC) mutants have reduced remyelination and impaired myelin debris clearance following demyelinating injury
Scott‐Hewitt, N., Folts, C. J., Hogestyn, J. M., Piester, G., Mayer-Pröschel, M., & Noble, M. (2017) · Human Molecular Genetics · doi:10.1093/hmg/ddx153 · Cited by 32 · see citing works
A novel pleiotropic effect of aspirin: Beneficial regulation of pro- and anti-inflammatory mechanisms in microglial cells
Kata, D., Földesi, I., Fehér, L. Z., Hackler, L., Puskás, L. G., & Gulya, K. (2017) · Brain Research Bulletin · doi:10.1016/j.brainresbull.2017.05.009 · Cited by 34 · see citing works
The TREM2-DAP12 signaling pathway in Nasu&ndash;Hakola disease: a molecular genetics perspective
Humphrey, M. B., Xing, J., & Titus, A. (2015) · Research and Reports in Biochemistry · doi:10.2147/rrbc.s58057 · Cited by 77 · see citing works
Upregulation of histone deacetylase 2 in laser capture nigral microglia in Parkinson's disease
Tan, Y., Delvaux, E., Nolz, J., Coleman, P. D., Chen, S., & Mastroeni, D. (2018) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2018.02.018 · Cited by 32 · see citing works
Extracellular vesicles can act as a potent immunomodulators of human microglial cells
Jonavičė, U., Tunaitis, V., Kriaučiūnaitė, K., Jarmalavičiūtė, A., & Pivoriūnas, A. (2019) · Journal of Tissue Engineering and Regenerative Medicine · doi:10.1002/term.2810 · Cited by 28 · see citing works
The involvement of microglia in Alzheimer's disease: a new dog in the fight
Moore, Z., Taylor, J. M., & Crack, P. J. (2019) · British Journal of Pharmacology · doi:10.1111/bph.14546 · Cited by 29 · see citing works
Alzheimer’s Disease Research Using Human Microglia
Lue, L., Beach, T. G., & Walker, D. G. (2019) · Cells · doi:10.3390/cells8080838 · Cited by 26 · see citing works
Self-citation
Association study of serum soluble TREM2 with vascular dementia in Chinese Han population
Wang, Q., Xu, Y., Qi, C., Liu, A., & Zhao, Y. (2019) · International Journal of Neuroscience · doi:10.1080/00207454.2019.1702548 · Cited by 26 · see citing works
Microglia and microglial-based receptors in the pathogenesis and treatment of Alzheimer’s disease
Wang, Z., & Weaver, D. F. (2022) · International Immunopharmacology · doi:10.1016/j.intimp.2022.109070 · Cited by 25 · see citing works
Heterozygous carriers of galactocerebrosidase mutations that cause Krabbe disease have impaired microglial function and defective repair of myelin damage
Noble, M., Scott‐Hewitt, N., & Folts, C. J. (2018) · Neural Regeneration Research · doi:10.4103/1673-5374.228712 · Cited by 23 · see citing works
Genetic discoveries and advances in late‐onset Alzheimer’s disease
Rezazadeh, M., Hosseinzadeh, H., Moradi, M., Esfahani, B. S., Talebian, S., Parvin, S., & Gharesouran, J. (2019) · Journal of Cellular Physiology · doi:10.1002/jcp.28372 · Cited by 22 · see citing works
The versatile role of TREM2 in regulating of microglia fate in the ischemic stroke
Ma, W.-Y., Wang, S., Wu, Q.-L., Zhou, X., Chu, S., & Chen, N. (2022) · International Immunopharmacology · doi:10.1016/j.intimp.2022.108733 · Cited by 19 · see citing works
Neuroprotective effects of nitidine in Parkinson's disease models through inhibiting microglia activation: role of the Jak2–Stat3 pathway
Wang, B., Wang, X.-Q., Yang, S., Liu, X., Feng, D., Lu, F., Zhu, Y., Lu, D., Lei, T., Ge, S., et al. (2016) · RSC Advances · doi:10.1039/c6ra11759g · Cited by 17 · see citing works
Elevated TREM2 mRNA expression in leukocytes in schizophrenia but not major depressive disorder
Yoshino, Y., Kawabe, K., Yamazaki, K., Watanabe, S., Numata, S., Mori, Y., Yoshida, T., Iga, J., Ohmori, T., & Ueno, S. (2016) · Journal of Neural Transmission · doi:10.1007/s00702-016-1560-3 · Cited by 15 · see citing works
Long-Term Pantethine Treatment Counteracts Pathologic Gene Dysregulation and Decreases Alzheimer's Disease Pathogenesis in a Transgenic Mouse Model
Baranger, K., van Gijsel‐Bonnello, M., Stephan, D., Carpentier, W., Rivera, S., Khrestchatisky, M., Gharib, B., Reggi, M. L. D., & Benech, P. (2019) · Neurotherapeutics · doi:10.1007/s13311-019-00754-z · Cited by 12 · see citing works
Nasu Hakola Disease: A Rare Cause of Dementia and Cystic Bone Lesions, Report of a New Turkish Family
Köseoğlu, E., Tepgeç, F., Yetkin, M. F., Uyguner, Z. O., Ekinci, A., Abdülrezzak, Ü., & Hanağası, H. A. (2017) · Nöro Psikiyatri Arşivi · doi:10.5152/npa.2017.19484 · Cited by 11 · see citing works
The Genetic Basis of Alzheimer's Disease
Hooli, B. V., & Tanzi, R. E. (2016) · Elsevier eBooks · doi:10.1016/b978-0-12-800105-9.00034-2 · Cited by 9 · see citing works
PU.1 dictates β-amyloid-induced TREM2 expression upregulation in microglia in a transgenic model of Alzheimer’s disease
Wei, Z., Pan, X., Cui, X., Zhang, J., Dai, X., Zeng, Y., & Chen, X. (2025) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2025.1537388 · Cited by 7 · see citing works
“The persistent upregulation of TREM2 and PU.1 expression in 5 × FAD mice may represent a defense response of the innate immune system to counterbalance amyloid plaque accumulation in the AD brain (Lue et al., 2015).”
CLEC4C p.K210del variant causes impaired cell surface transport in plasmacytoid dendritic cells of amyotrophic lateral sclerosis
Lim, S. M., Kim, Y.-E., Choi, W. J., Oh, K., Noh, M., Kwon, M., Nahm, M., Kim, N., Ki, C., & Kim, S. H. (2016) · Oncotarget · doi:10.18632/oncotarget.7886 · Cited by 6 · see citing works
Computational saturation mutagenesis to explore the effect of pathogenic mutations on extra-cellular domains of TREM2 associated with Alzheimer’s and Nasu-Hakola disease
Swain, P. S., Panda, S., Pati, S., & Dehury, B. (2023) · Journal of Molecular Modeling · doi:10.1007/s00894-023-05770-7 · Cited by 6 · see citing works
The Genetic Basis of Alzheimer’s Disease
Hooli, B. V., & Tanzi, R. E. (2016) · Elsevier eBooks · doi:10.1016/b978-0-12-802173-6.00002-2 · Cited by 6 · see citing works
Nasu Hakola Disease: A Rare Cause of Dementia and Cystic Bone Lesions, Report of a New Turkish Family
Köseoğlu, E., Tepgeç, F., Yetkin, M. F., Uyguner, O., Ekinci, A., Abdülrezzak, Ü., & Hanagasi, H. A. (2018) · Nöro Psikiyatri Arşivi · doi:10.29399/npa.19484 · Cited by 6 · see citing works
Pathomechanismen und klinische Aspekte der frontotemporalen Lobärdegeneration
Bürger, K., Arzberger, T., Stephan, J., Levin, J., & Edbauer, D. (2016) · Der Nervenarzt · doi:10.1007/s00115-016-0259-x · Cited by 4 · see citing works
Towards defining the Mechanisms of Alzheimer's disease based on a contextual analysis of molecular pathways
Richens, J. L., Bramble, J. P., Spencer, H. L., Cantlay, F., Butler, M., & O’Shea, P. (2016) · Global Medical Genetics · doi:10.3934/genet.2016.1.25 · Cited by 3 · see citing works
Beyond plaques and tangles: The role of immune cell dysfunction in Alzheimer's disease
Hussain, N., Khan, M. M., Sharma, A., Singh, R. K., & Khan, R. H. (2025) · Neurochemistry International · doi:10.1016/j.neuint.2025.105947 · Cited by 2 · see citing works
TREM2 Recognition of Candidalysin Orchestrates Mucosal Immunity in Oropharyngeal CandidiasisPreprint
Deng, W., Chen, Y., Liu, S., Lin, K., Zhang, K., Wang, D., Yu, Z., Zhao, W., Xu, Y., Wang, X., et al. (2024) · Research Square · doi:10.21203/rs.3.rs-4137807/v1 · Cited by 1 · see citing works
Morphological, functional and immunomodulatory effects of rosuvastatin and aspirin in cultured microglial cells
Kata, D. (2017) · doi:10.14232/phd.4142
1359 Hair growth is induced by blockade of macrophage-derived oncostatin M and downstream JAK-STAT5 signaling in hair follicle stem cells
Wang, E., & Christiano, A. M. (2018) · Journal of Investigative Dermatology · doi:10.1016/j.jid.2018.03.1376
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Single-Nucleus Transcriptomics Analysis Identifies Sex-Dichotomous Pathological Axes in Alzheimer’s Disease: Female Homeostatic Failure versus Male Neuroimmune ActivationPreprint
Zhou, Z., Jiang, C., & Chen, Z. (2026) · Research Square · doi:10.21203/rs.3.rs-9504119/v1

TREM2: Potential therapeutic targeting of microglia for Alzheimer's disease
Li, Y., Xu, H., Wang, H., Yang, K., Luan, J., & Wang, S. (2023) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2023.115218 · Cited by 128 · see citing works
TREM2 and microglial immunity in Alzheimer’s disease: mechanisms, genetics, and therapeutic opportunities
Wang, T., Liu, X., Wang, X., Hua, F., & Yan, L. (2026) · Frontiers in Immunology · doi:10.3389/fimmu.2026.1739875 · Cited by 14 · see citing works
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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
Untangling the Role of TREM2 in Conjugation with Microglia in Neuronal Dysfunction: A Hypothesis on a Novel Pathway in the Pathophysiology of Alzheimer’s Disease
Basha, S. C., Ramaiah, M. J., & Rao, K. S. J. (2023) · Journal of Alzheimer s Disease · doi:10.3233/jad-221070 · Cited by 22 · see citing works
TREM2 signalling as a multifaceted player in brain homoeostasis and a potential target for Alzheimer's disease treatment
Ayyubova, G. (2023) · European Journal of Neuroscience · doi:10.1111/ejn.15914 · Cited by 20 · see citing works

Authors: Lue, L.-F., Schmitz, C., & Walker, D. G.
Affiliations: Banner Sun Health Research Institute (US)
ORCID: Schmitz, C.
Walker, D.G.
Venue: Neuroscience
Publisher: Elsevier BV
Published: 2015-08
Volume: 302
Pages: 138-150
ISSN: 0306-4522 (ISSN-L)
DOI: 10.1016/j.neuroscience.2014.09.050
OpenAlex: W2050445129
Cited by: 63
References: 89
Citations by year: 2026: 1 · 2025: 2 · 2024: 3 · 2023: 3 · 2022: 3 · 2021: 3 · 2020: 2 · 2019: 5 · 2018: 12 · 2017: 9 · 2016: 11 · 2015: 9
FWCI: 0.78
Type: journal article
Language: en
Open access: closed
Licence: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
Locations: Neuroscience (publishedVersion)
PubMed (publishedVersion)
Funders: The Arizona Department of Health Services
National Institute on Aging
Arizona Alzheimer Research Consortium
Arizona State Department of Health Service
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: TREM2, DAP12, microglia, Alzheimer's disease, phagocytosis, amyloid-beta, mitochondrial Hsp60, microglial activation, neuroinflammation, neurodegenerative diseases, frontotemporal dementia, Parkinson's disease, amyotrophic lateral sclerosis
MeSH terms: Alzheimer Disease, Gene Expression Regulation, Humans, Membrane Glycoproteins, Mutation, Receptors, Immunologic, Microglia

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What happens to microglial TREM2 in Alzheimer’s disease: Immunoregulatory turned into immunopathogenic?

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