GPR40 was utilized as the drug target to the treatment of diabetes, but the function and mechanisms ameliorating the Alzheimer's disease (AD) remain unknown. In present study, the typical APP/PS1 mouse model was applied to explore the function and mechanism of GPR40 in AD. GPR40 agonist GW9508 and antagonist GW1100 were respectively given by i.c.v. injection to activate/inhibit the GPR40 in the brain of APP/PS1 mice which illustrated the function and mechanism of GPR40 in ameliorating AD symptoms. Morris water maze test, step-through test, Y-maze spontaneous alternation test, open field test and new object recognition test were used to test the cognitive function and memory ability of mice, while molecular biology experiments such as Western blot, immunofluorescence, JC-1 were used to detect the corresponding changes of signal pathways. The results revealed that treatment with GW9508 could significantly ameliorate cognitive deficits of APP/PS1 mice, upregulate the expression levels of cAMP, p-CREB and neurotrophic factors in vivo, while GW9508 also ameliorate Aβ1-42-induced neuron damage and downregulate the expression levels of pathological protein such as p-JNK, JNK and apoptosis-related proteins such as IL-6, IL-1β, TNF-α and caspase-3 in vitro. Meanwhile, high-content screening also showed that GW9508 promoted the cellular differentiation of SH-SY5Y cells, while GW1100 reversed the effects of GW9508. These results suggested that GPR40 was an underlying therapeutic target for the treatment of AD and GPR40 agonist could be explored as the emerging AD therapeutic drug.

中文翻译：

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GW9508通过cAMP-CREB和JNK途径改善了阿尔茨海默氏病APPswe / PS1dE9小鼠模型的认知障碍。

GPR40被用作治疗糖尿病的药物靶标，但改善阿尔茨海默氏病（AD）的功能和机制仍然未知。在本研究中，典型的APP / PS1小鼠模型被用于探讨GPR40在AD中的功能和机制。通过icv注射分别给予GPR40激动剂GW9508和拮抗剂GW1100以激活/抑制APP / PS1小鼠脑中的GPR40，这说明了GPR40在改善AD症状中的功能和机制。使用莫里斯水迷宫测试，逐步测试，Y迷宫自发交替测试，开放视野测试和新物体识别测试来测试小鼠的认知功能和记忆能力，而分子生物学实验例如蛋白质印迹，免疫荧光，JC -1被用来检测信号通路的相应变化。结果表明，GW9508处理可显着改善APP / PS1小鼠的认知缺陷，上调体内cAMP，p-CREB和神经营养因子的表达水平，而GW9508还可改善Aβ1-42诱导的神经元损伤并下调表达水平在体外检测p-JNK，JNK等病理蛋白和IL-6，IL-1β，TNF-α和caspase-3等凋亡相关蛋白。同时，高含量筛选还表明，GW9508促进了SH-SY5Y细胞的细胞分化，而GW1100逆转了GW9508的作用。这些结果表明，GPR40是治疗AD的潜在治疗靶标，GPR40激动剂可以作为新兴的AD治疗药物进行探索。GW9508还改善了Aβ1-42诱导的神经元损伤，并下调了病理蛋白（例如p-JNK，JNK和细胞凋亡相关蛋白（例如IL））的表达，从而上调了体内cAMP，p-CREB和神经营养因子的表达水平。 -6，IL-1β，TNF-α和caspase-3体外。同时，高含量筛选还表明，GW9508促进了SH-SY5Y细胞的细胞分化，而GW1100逆转了GW9508的作用。这些结果表明，GPR40是治疗AD的潜在治疗靶标，GPR40激动剂可以作为新兴的AD治疗药物进行探索。GW9508还改善了Aβ1-42诱导的神经元损伤，并下调了病理蛋白（例如p-JNK，JNK和细胞凋亡相关蛋白（例如IL））的表达，从而上调了体内cAMP，p-CREB和神经营养因子的表达水平。 -6，IL-1β，TNF-α和caspase-3体外。同时，高含量筛选还表明，GW9508促进了SH-SY5Y细胞的细胞分化，而GW1100逆转了GW9508的作用。这些结果表明，GPR40是治疗AD的潜在治疗靶标，GPR40激动剂可以作为新兴的AD治疗药物进行探索。JNK和细胞凋亡相关蛋白，如IL-6，IL-1β，TNF-α和caspase-3的体外表达。同时，高含量筛选还表明，GW9508促进了SH-SY5Y细胞的细胞分化，而GW1100逆转了GW9508的作用。这些结果表明，GPR40是治疗AD的潜在治疗靶标，GPR40激动剂可以作为新兴的AD治疗药物进行探索。JNK和细胞凋亡相关蛋白，如IL-6，IL-1β，TNF-α和caspase-3的体外表达。同时，高含量筛选还表明，GW9508促进了SH-SY5Y细胞的细胞分化，而GW1100逆转了GW9508的作用。这些结果表明，GPR40是治疗AD的潜在治疗靶标，GPR40激动剂可以作为新兴的AD治疗药物进行探索。