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.
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Funding
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).
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All procedures performed in this study involving animals were in accordance with the ethical standards of Nanjing First Hospital.
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Jiang, T., Zhang, YD., Gao, Q. et al. TREM2 Ameliorates Neuronal Tau Pathology Through Suppression of Microglial Inflammatory Response. Inflammation 41, 811–823 (2018). https://doi.org/10.1007/s10753-018-0735-5
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DOI: https://doi.org/10.1007/s10753-018-0735-5