Jiang Yanhua, Li Zhe, Ma Hong, Cao Xuezhao, Liu Fang, Tian Ayong, Sun Xijia, Li Xiaoqian, Wang Jun
Department of Anesthesiology, the First Hospital of China Medical University, Shenyang, China.
Department of Neurology, the First Hospital of China Medical University, Shenyang, China.
Cell Physiol Biochem. 2018;46(4):1398-1411. doi: 10.1159/000489155. Epub 2018 Apr 18.
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.
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 (IL)-1β were measured at each time point. Ionized calcium-binding adapter molecule 1 (Iba-1), microglial M2 phenotype marker Arg1, synaptophysin, tau hyperphosphorylation (T396), and glycogen synthase kinase-3β (GSK-3β) were also examined in the hippocampus.
Surgical trauma induced an exacerbated cognitive impairment and enhanced hippocampal IL-1β 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-1β, ameliorated T396 expression, inhibited the activity of GSK-3β, and improved sickness behavior. Increased Arg1 expression and a high level of synaptophysin were also observed in the transgenic mice following TREM2 overexpression.
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.
背景/目的：触发受体表达上调基因2（TREM2）通过与TREM2适配体DAP12相互作用，在调节小胶质细胞功能中起关键作用。新出现的证据表明，TREM2可通过抑制小胶质细胞介导的细胞因子产生来抑制神经炎症反应。本研究调查了TREM2在野生型（WT）和淀粉样前体蛋白（APP） Swe/早老素1（PS1）dE9小鼠手术诱导的认知缺陷和神经炎症反应中的潜在作用。
成年APP Swe/PS1dE9转基因雄性小鼠（阿尔茨海默病经典转基因模型，3个月大）及其年龄匹配的WT小鼠接受编码小鼠TREM2基因的脑内慢病毒颗粒，然后在慢病毒颗粒注射后1个月接受部分肝切除术。在术后第3、7和14天，通过旷场试验和莫里斯水迷宫试验评估行为变化。在每个时间点测量海马体中的TREM2、DAP12和白细胞介素（IL）-1β。还检测了海马体中的离子钙结合衔接分子1（Iba-1）、小胶质细胞M2表型标志物精氨酸酶1（Arg1）、突触素、tau蛋白过度磷酸化（T396）和糖原合酶激酶-3β（GSK-3β）。
手术创伤在术后第3天和第7天导致转基因小鼠认知障碍加剧，海马体IL-1β表达增强。在术后第3、7和14天也发现TREM2水平相应下降。TREM2过表达下调了IL-1β水平，改善了T396表达，抑制了GSK-3β的活性，并改善了疾病行为。在TREM2过表达后的转基因小鼠中还观察到Arg1表达增加和突触素水平升高。
在该啮齿动物模型中，TREM2的下调加剧了手术诱导的认知缺陷并夸大了神经炎症反应。TREM2过表达可能通过减少促炎细胞因子的相关产生、抑制tau蛋白过度磷酸化和增强突触素表达来减弱这些影响。
