TREM2 Ameliorates Neuronal Tau Pathology Through Suppression of Microglial Inflammatory Response
TREM2 Ameliorates Neuronal Tau Pathology Through Suppression of Microglial Inflammatory Response
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TREM2 通过抑制小胶质细胞炎症反应来改善神经元 Tau 病理学。
DOI：
10.1007/s10753-018-0735-5
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发表时间：
2018-06-01
期刊：
影响因子：
5.1
通讯作者：
Zhou, Jun-Shan
中科院分区：
文献类型：
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作者：
Jiang, Teng;Zhang, Ying-Dong;Zhou, Jun-Shan
作为最近发现的阿尔茨海默病（AD）易感基因，髓样细胞表达的触发受体2（TREM 2）编码在小胶质细胞上独特表达的免疫受体，作为小胶质细胞功能（包括吞噬和炎症反应）的调节剂起作用。几条证据表明，TREM 2上调，并与AD患者脑中的tau病理正相关。同时，我们最近的研究表明，敲低TREM 2显著加剧了P301 S-tau转基因小鼠脑中神经元tau的过度磷酸化，这意味着TREM 2可能对AD背景下的tau病理发挥保护作用。然而，这一观察结果背后的确切机制在很大程度上仍不清楚。在这项研究中，通过采用小胶质细胞-神经元共培养模型，我们表明脂多糖诱导的小胶质细胞炎症反应通过激活主要的tau激酶糖原合酶激酶3 β导致神经元中的tau过度磷酸化，证实了激活的小胶质细胞对tau病理学进展的致病作用。更重要的是，通过用慢病毒介导的策略操纵小胶质细胞中的TREM 2水平，我们证明了TREM 2通过抑制小胶质细胞炎症反应来改善活化的小胶质细胞对神经元tau过度磷酸化的病理作用。总之，这些发现揭示了TREM 2保护免受tau病理学影响的潜在机制，并强调TREM 2是AD的潜在治疗靶点。
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 3 beta, 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.