Upregulation of TREM2 Ameliorates Neuroinflammatory Responses and Improves Cognitive Deficits Triggered by Surgical Trauma in Appswe/PS1dE9 Mice
Upregulation of TREM2 Ameliorates Neuroinflammatory Responses and Improves Cognitive Deficits Triggered by Surgical Trauma in Appswe/PS1dE9 Mice
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DOI：
10.1159/000489155
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发表时间：
2018-01-01
影响因子：
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通讯作者：
Wang, Jun
中科院分区：
文献类型：
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作者：
Jiang, Yanhua;Li, Zhe;Wang, Jun
背景/目的：TREM2通过与TREM2的适配子DAP12相互作用，在调节小胶质细胞功能中发挥重要作用。新的证据表明，TREM2可以通过抑制小胶质细胞介导的细胞因子的产生来抑制神经炎性反应。这项研究探讨了TREM2在野生型(WT)和APPswe/PS1dE9小鼠手术诱导的认知障碍和神经炎性反应中的潜在作用。方法：成年APPsWE/PS1dE9转基因雄性小鼠(3月龄)及其同龄WT小鼠接受编码小鼠TREM2基因的慢病毒颗粒脑内注射，并于注射慢病毒颗粒后1个月行肝部分切除。分别于术后第3、7、14天进行旷场实验和Morris水迷宫实验，检测各时间点大鼠海马区TREM2、DAP12和IL-1-113的表达。海马区还检测了离子钙结合适配器分子1(Iba-1)、小胶质细胞M2表型标志物Arg1、突触素、tau过度磷酸化(T396)和糖原合成酶-3β(GSK-3β)。结果：手术创伤后第3、7天转基因小鼠认知功能障碍加重，海马区IL-1β表达增强。术后第3、7、14天，TREM2表达水平也相应下降。TREM2过表达下调IL-β水平，改善T396表达，抑制GSK-3β活性，改善疾病行为。在TREM2过表达后的转基因小鼠中也观察到Arg1表达增加和突触素水平升高。结论：在这种啮齿动物模型中，TREM2的下调加剧了手术诱导的认知障碍和夸大的神经炎性反应。TREM2的过度表达可能通过减少相关的促炎细胞因子的产生，抑制tau的过度磷酸化，并增强突触素的表达来减弱这些影响。(C)2018年作者(S)巴塞尔，S卡格尔股份公司发稿。
Background/Aims: TREM2 plays a crucial role in modulating microglial function through interaction with DAP12, the adapter for TREM2. Emerging evidence has demonstrated that TREM2 could suppress neuroinflammatory responses by repression of microglia-mediated cytokine production. This study investigated the potential role of TREM2 in surgery-induced cognitive deficits and neuroinflammatory responses in wild-type (WT) and APPswe/PS1dE9 mice. Methods: Adult APPswe/PS1dE9 transgenic male mice (a classic transgenic model of Alzheimer's disease, 3 months old) and their age-matched WT mice received intracerebral lentiviral particles encoding the mouse TREM2 gene and then were subjected to partial hepatectomy at 1 month after the lentiviral particle injection. The behavioral changes were evaluated with an open-field test and Morris water maze test on postoperative days 3, 7, and 14. Hippocampal TREM2, DAP12, and interleukin (1)-113 were measured at each time point. Ionized calcium-binding adapter molecule 1 (Iba-1), microglial M2 phenotype marker Argl, synaptophysin, tau hyperphosphorylation (T396), and glycogen synthase kinase-3 beta (GSK-3 beta) were also examined in the hippocampus. Results: Surgical trauma induced an exacerbated cognitive impairment and enhanced hippocampal IL-1 beta expression in the transgenic mice on postoperative days 3 and 7. A corresponding decline in the levels of TREM2 was also found on postoperative days 3, 7, and 14. Overexpression of TREM2 downregulated the levels of IL-beta, ameliorated T396 expression, inhibited the activity of GSK-3 beta, and improved sickness behavior. Increased Arg1 expression and a high level of synaptophysin were also observed in the transgenic mice following TREM2 overexpression. Conclusion: The downregulation of TREM2 exacerbated surgery-induced cognitive deficits and exaggerated neuroinflammatory responses in this rodent model. Overexpression of TREM2 potentially attenuated these effects by decreasing the associated production of proinflammatory cytokines, inhibiting tau hyperphosphorylation, and enhancing synaptophysin expression. (C) 2018 The Author(s) Published by S Karger AG, Basel.