Cited by 176Neuroinflammation and Neurodegeneration MechanismsAlzheimer's disease research and treatmentsNeurological Disease Mechanisms and Treatments

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TREM2 modifies microglial phenotype and provides neuroprotection in P301S tau transgenic mice

Jiang, Teng, Zhang, Ying-Dong, Chen, Qi, Gao, Qing, Zhu, Xi-Chen, Zhou, Jun-Shan, Shi, Jian-Quan, Lu, Huan, Tan, Lan, Yu, Jin-Tai·2016·Neuropharmacology

DOI 10.1016/j.neuropharm.2016.01.028

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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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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
ORCID: Jiang, Teng
Chen, Qi
Zhu, Xi-Chen
Shi, Jian-Quan
Lu, Huan
Tan, Lan
Yu, Jin-Tai
Venue: Neuropharmacology
Publisher: Elsevier BV
Published: 2016-06
Volume: 105
Pages: 196-206
ISSN: 0028-3908 (ISSN-L)
DOI: 10.1016/j.neuropharm.2016.01.028
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: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
www.elsevier.com/legal/tdmrep-license (tdm)
doi.org/10.15223/policy-017 (stm-asf)
doi.org/10.15223/policy-037 (stm-asf)
doi.org/10.15223/policy-012 (stm-asf)
doi.org/10.15223/policy-029 (stm-asf)
doi.org/10.15223/policy-004 (stm-asf)
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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TREM2 modifies microglial phenotype and provides neuroprotection in P301S tau transgenic mice

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