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TREM2 modifies microglial phenotype and provides neuroprotection in P301S tau transgenic mice
Abstract
As a novel risk gene for Alzheimer's disease (AD), triggering receptor expressed on myeloid cells 2 (TREM2) gene encodes a type I transmembrane receptor that is uniquely expressed by the microglia in the brain. Emerging evidence indicates a strong association between TREM2 and tau pathology in the cerebral spinal fluid or brain tissue of AD patients. In line with these clinical findings, we found that TREM2 was upregulated in the brain of P301S mice, an animal model of tau pathology, during disease progression. However, despite this information, the precise role of TREM2 in tau pathology remains largely unknown. In our recent studies, we revealed that silencing microglial TREM2 expression in P301S mice exacerbated spatial cognitive deficits and tau pathology. Based on this evidence, we hypothesized that TREM2 might exert a protective effect in tau-related neurodegenerative diseases. In the present study, to test this hypothesis, a lentiviral-mediated strategy was employed to selectively overexpress TREM2 on microglia in the brain of P301S mice. For the first time, we showed that TREM2 overexpression rescued spatial cognitive impairments and ameliorated neuropathologies including neuronal and synaptic loss as well as tau hyperphosphorylation. Meanwhile, this protective effect was likely attributed to the suppression of neuroinflammation and subsequent attenuation of tau kinase activity, since the expression of pro-inflammatory cytokines including Tnf, Il1b and Il6 as well as the activity of tau kinase including glycogen synthase kinase 3β and cyclin-dependent kinase 5 was significantly reduced following TREM2 overexpression. Additionally, the suppressed neuroinflammation might be ascribed to the M2 activation of microglia induced by TREM2, as the expression of M2 phenotype makers including Arg1, Retnla, Il4 and Il10 was markedly increased. Taken together, these findings support the concept of TREM2 as a valuable target against AD as well as other tau-related neurodegenerative diseases.
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“overexpressing murine TREM2 in microglia is found to reduce tau hyperphosphorylation in the mid-disease stage in P301S mice68.”
From Interplay between innate immunity and Alzheimer disease: APOE and TREM2 in the spotlight (2018) · cites this paper as [68]
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Cites
TREM2 Variants in Alzheimer's Disease
Guerreiro, R., Wojtas, A., Bras, J., Carrasquillo, M., Rogaeva, E., Majounie, E., Cruchaga, C., Sassi, C., Kauwe, J. S. K., Younkin, S., et al. (2013) · New England Journal of Medicine · doi:10.1056/nejmoa1211851 · Cited by 3,020
Variant of TREM2 Associated with the Risk of Alzheimer's Disease
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TREM2 Lipid Sensing Sustains the Microglial Response in an Alzheimer’s Disease Model
Wang, Y., Cella, M., Mallinson, K., Ulrich, J. D., Young, K. L., Robinette, M. L., Gilfillan, S., Krishnan, G. M., Sudhakar, S., Zinselmeyer, B. H., et al. (2015) · Cell · doi:10.1016/j.cell.2015.01.049 · Cited by 1,736
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Tangle and neuron numbers, but not amyloid load, predict cognitive status in Alzheimer’s disease
Giannakopoulos, P., Herrmann, F. R., Bussière, T., Bouras, C., Kövari, E., Perl, D. P., Morrison, J. H., Gold, G., & Hof, P. R. (2003) · Neurology · doi:10.1212/01.wnl.0000063311.58879.01 · Cited by 1,118
TREM2 mutations implicated in neurodegeneration impair cell surface transport and phagocytosis
Kleinberger, G., Yamanishi, Y., Suárez-Calvet, M., Czirr, E., Lohmann, E., Cuyvers, E., Struyfs, H., Pettkus, N., Wenninger-Weinzierl, A., Mazaheri, F., et al. (2014) · Science Translational Medicine · doi:10.1126/scitranslmed.3009093 · Cited by 798
TREMs in the immune system and beyond
Colonna, M. (2003) · Nature Reviews Immunology · doi:10.1038/nri1106 · Cited by 701
Alternatively activated microglia and macrophages in the central nervous system
Franco, R., & Fernández‐Suárez, D. (2015) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2015.05.003 · Cited by 674
TREM2 sustains microglial expansion during aging and response to demyelination
Poliani, P. L., Wang, Y., Fontana, E., Robinette, M. L., Yamanishi, Y., Gilfillan, S., & Colonna, M. (2015) · Journal of Clinical Investigation · doi:10.1172/jci77983 · Cited by 525
Synaptic degeneration in Alzheimer's disease
Arendt, T. (2009) · Acta Neuropathologica · doi:10.1007/s00401-009-0536-x · Cited by 517
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Disease-Associated Microglia: A Universal Immune Sensor of Neurodegeneration
Deczkowska, A., Keren-Shaul, H., Weiner, A., Colonna, M., Schwartz, M., & Amit, I. (2018) · Cell · doi:10.1016/j.cell.2018.05.003 · Cited by 1,474
Interplay between innate immunity and Alzheimer disease: APOE and TREM2 in the spotlight
Shi, Y., & Holtzman, D. M. (2018) · Nature Reviews Immunology · doi:10.1038/s41577-018-0051-1 · Cited by 595
Amyloid-β-independent regulators of tau pathology in Alzheimer disease
van der Kant, R., Goldstein, L. S. B., & Ossenkoppele, R. (2020) · Nature reviews. Neuroscience · doi:10.1038/s41583-019-0240-3 · Cited by 580
Inflammatory Response in the CNS: Friend or Foe?
Sochocka, M., Diniz, B. S., & Leszek, J. (2017) · Molecular Neurobiology · doi:10.1007/s12035-016-0297-1 · Cited by 573
New insights into the role of TREM2 in Alzheimer’s disease
Gratuze, M., Leyns, C. E. G., & Holtzman, D. M. (2018) · Molecular Neurodegeneration · doi:10.1186/s13024-018-0298-9 · Cited by 489
Metadata
- Authors
- Jiang, T., Zhang, Y.-D., Chen, Q., Gao, Q., Zhu, X.-C., Zhou, J.-S., Shi, J.-Q., Lu, H., Tan, L., & Yu, J.-T.
- Affiliations
- University of California, San Francisco (US)
- Nanjing Medical University (CN)
- Nanjing First Hospital (CN)
- Qingdao Municipal Hospital (CN)
- Qingdao University (CN)
- Corresponding author
- Tan, Lan
- Yu, Jin-Tai
- Venue
- Neuropharmacology
- Publisher
- Elsevier BV
- Published
- 2016-06
- Volume
- 105
- Pages
- 196-206
- ISSN
- 0028-3908 (ISSN-L)
- OpenAlex
- W2246389678
- Cited by
- 176
- References
- 40
- Citations by year
- 2026: 4 · 2025: 13 · 2024: 21 · 2023: 20 · 2022: 17 · 2021: 20 · 2020: 19 · 2019: 21 · 2018: 18 · 2017: 18 · 2016: 5
- FWCI
- 11.31
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- Locations
- Neuropharmacology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Natural Science Foundation of China (81501092, 81471309, 81571245, 81500916)
- Natural Science Foundation of Jiangsu Province (BK20150091, BK20151084)
- China Postdoctoral Science Foundation (2015M580448)
- Qingdao Key Health Discipline Development Fund
- Qingdao Outstanding Health Professional Development Fund
- Shandong Provincial Collaborative Innovation Center for Neurodegenerative Disorders
- Topics
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Neurology › Neurological Disease Mechanisms and Treatments
- Keywords
- TREM2, microglia, P301S tau transgenic mice, tau pathology, Alzheimer's disease, neuroprotection, neuroinflammation, tau hyperphosphorylation, glycogen synthase kinase-3β, cyclin-dependent kinase 5, inflammatory cytokines, lentiviral overexpression
- MeSH terms
- Neuroprotection, Glycogen Synthase Kinase 3 beta, Alzheimer Disease, Animals, Brain, Disease Models, Animal, Encephalitis, Exploratory Behavior, Genetic Vectors, Male, Membrane Glycoproteins, Mice, Inbred C57BL, Mice, Transgenic, Phenotype, Phosphorylation, Receptors, Immunologic, Lentivirus, tau Proteins, Microglia, Maze Learning, Inflammation Mediators, Cyclin-Dependent Kinase 5, Mice
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