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首页> 美国卫生研究院文献>Aging (Albany NY) >TREM2 ameliorates neuroinflammatory response and cognitive impairment via PI3K/AKT/FoxO3a signaling pathway in Alzheimer’s disease mice
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TREM2 ameliorates neuroinflammatory response and cognitive impairment via PI3K/AKT/FoxO3a signaling pathway in Alzheimer’s disease mice

机译：Trem2通过PI3K / AKT / FOXO3A信号通路在阿尔茨海默病小鼠中改善神经炎性反应和认知障碍

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Triggering receptor expressed on myeloid cells 2 (TREM2) has been shown with a neuroprotective function against inflammation and neuronal injury in Alzheimer’s disease (AD). However, the TREM2 induced anti-inflammatory mechanism is still not well known. In this study it has been demonstrated that the expression of TREM2 was upregulated in hippocampus of 5xFAD mice, whereas TREM2 knock-out mediated by AAV significantly increased the levels of pro-inflammatory cytokines and aggravated cognitive defect. Additionally, FoxO3a, a downstream member of the PI3K/AKT pathway, could be activated by TREM2 defect via the PI3K/AKT signaling in 5xFAD mice. That suggests TREM2-induced protection is associated with the PI3K-FoxO3a axis. On the contrary, overexpression of TREM2 alleviated the LPS-induced inflammatory response and induced M2 phenotype microglia in vitro. This phenomenon can be abolished by applying the PI3K inhibitor LY294002, suggesting FoxO3a not only participates in TREM2-induced anti-inflammation response, but is also involved in regulating the phenotype of microglia. Taken together, our results show that the protective functions of TREM2, both in inflammatory response and cognitive impairment as well as in the decrease of M1 phenotype microglia, are related to PI3K/AKT/FoxO3a signaling pathway in AD mice.
机译：已经显示出在骨髓细胞2（Thread2）上表达的触发受体具有针对阿尔茨海默病（AD）的炎症和神经元损伤的神经保护功能。然而，Trem2诱导的抗炎机制仍然是不公知的。在这项研究中，已经证明了Trem2的表达在5xFAD小鼠的海马中上调，而Derm2被AAV介导的催眠细胞因子和加重认知缺陷的水平显着增加。另外，PI3K / AKT途径的下游构件FoxO3a可以通过5xFAD小鼠的PI3K / AKT信号传导通过Trem2缺陷激活。这表明Trem2诱导的保护与PI3K-FOXO3A轴相关联。相反，Trem2的过度表达减轻了LPS诱导的炎症反应和体外诱导的M2表型微胶质。通过应用PI3K抑制剂Ly294002可以消除这种现象，表明FoxO3a不仅参与Trem2诱导的抗炎反应，而且还参与调节小胶质细胞的表型。我们的结果表明，TREM2的保护功能，既炎症反应和认知障碍以及在M1表型微胶质细胞的减少中，都与AD小鼠中的PI3K / AKT / FOXO3A信号传导途径有关。

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