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Inflammation

, Volume 41, Issue 3, pp 811–823 | Cite as

TREM2 Ameliorates Neuronal Tau Pathology Through Suppression of Microglial Inflammatory Response

  • Teng JiangEmail author
  • Ying-Dong Zhang
  • Qing Gao
  • Zhou Ou
  • Peng-Yu Gong
  • Jian-Quan Shi
  • Liang Wu
  • Jun-Shan ZhouEmail author
ORIGINAL ARTICLE

Abstract

As a recently identified susceptibility gene for Alzheimer’s disease (AD), triggering receptor expressed on myeloid cells 2 (TREM2) encodes an immune receptor that is uniquely expressed on microglia, functioning as a modulator of microglial functions including phagocytosis and inflammatory response. Several lines of evidence suggest that TREM2 is upregulated and positively correlates with tau pathology in the brains of AD patients. Meanwhile, our recent study showed that knockdown of TREM2 markedly exacerbated neuronal tau hyperphosphorylation in the brains of P301S-tau transgenic mice, implying that TREM2 might exert a protective role against tau pathology under AD context. However, the precise mechanisms underlying this observation remain largely unclear. In this study, by employing a microglial-neuronal co-culture model, we showed that microglial inflammatory response induced by lipopolysaccharide led to tau hyperphosphorylation in neurons via activation of a major tau kinase glycogen synthase kinase 3β, confirming the pathogenic effects of activated microglia on the progression of tau pathology. More importantly, by manipulating TREM2 levels in microglia with a lentiviral-mediated strategy, we demonstrated that TREM2 ameliorated the pathological effects of activated microglia on neuronal tau hyperphosphorylation via suppression of microglial inflammatory response. Taken together, these findings uncover the underlying mechanisms by which TREM2 protects against tau pathology and highlight TREM2 as a potential therapeutic target for AD.

KEY WORDS

Alzheimer’s disease TREM2 tau pathology microglia inflammation tau kinase 

Notes

Funding Information

This work was supported by the National Natural Science Foundation of China (81501092, 81500916), Natural Science Foundation of Jiangsu Province (BK20150091), “Six Talent Summit” Foundation of Jiangsu Province (2016-WSN-180), Youth Medical Talent Program of Jiangsu Province (QNRC2016068, QNRC2016079), Medical Innovation Team of Jiangsu Province (CXTDA2017030), and Nanjing Medical Science and Technology Development Foundation for Distinguished Young Scholars (JQX17008).

Compliance with Ethical Standards

All procedures performed in this study involving animals were in accordance with the ethical standards of Nanjing First Hospital.

Conflict of Interest

The authors declare that there is no conflict of interest.

Supplementary material

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ESM 1 (DOCX 16 kb)
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Fig. S1

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High-resolution image (TIFF 689 kb)

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Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  • Teng Jiang
    • 1
    Email author
  • Ying-Dong Zhang
    • 1
  • Qing Gao
    • 1
  • Zhou Ou
    • 1
  • Peng-Yu Gong
    • 1
  • Jian-Quan Shi
    • 1
  • Liang Wu
    • 1
  • Jun-Shan Zhou
    • 1
    Email author
  1. 1.Department of Neurology, Nanjing First HospitalNanjing Medical UniversityNanjingPeople’s Republic of China

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