RATIONALE Alzheimer's disease (AD) is an age-related neurodegenerative disease characterized by progressive cognitive dysfunction and memory impairment. G protein-coupled receptor 40 (GPR40) is expressed in brain in addition to periphery and is associated with cognitive function such as space orientation, memory, and learning. However, the effects and mechanisms of GPR40 agonist in improving the AD progression remain largely unknown. OBJECTIVES The present study aimed to investigate the therapeutic effects and mechanisms of a potent and selective GPR40 agonist TAK-875 on the APPswe/PS1dE9 mice. RESULTS The results showed that intracerebroventricular administration of TAK-875 significantly rescued cognitive deficits in APPswe/PS1dE9 mice, and these effects may be mediated by the regulation of phospholipase C/protein kinase C signaling pathway, which enhanced α-secretase ADAM10 activity, promoted amyloid precursor protein non-amyloidogenic processing pathway, and reduced β-amyloid production. CONCLUSIONS These results suggest that GPR40 may be a potential therapeutic target for AD, and GPR40 agonists may become promising AD drugs in the future.

中文翻译：

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GPR40 受体激动剂 TAK-875 可改善 APPswe/PS1dE9 小鼠的认知缺陷并减少 β-淀粉样蛋白的产生。


基本原理阿尔茨海默病（AD）是一种与年龄相关的神经退行性疾病，其特征是进行性认知功能障碍和记忆障碍。 G 蛋白偶联受体 40 (GPR40) 在大脑和外周细胞中表达，与空间定向、记忆和学习等认知功能相关。然而，GPR40激动剂在改善AD进展方面的作用和机制仍然很大程度上未知。目的 本研究旨在探讨强效选择性 GPR40 激动剂 TAK-875 对 APPswe/PS1dE9 小鼠的治疗效果和机制。结果结果显示，侧脑室注射TAK-875可显着挽救APPswe/PS1dE9小鼠的认知缺陷，这些作用可能是通过调节磷脂酶C/蛋白激酶C信号通路介导的，增强了α-分泌酶ADAM10的活性，促进淀粉样蛋白的形成。前体蛋白非淀粉样蛋白形成加工途径，并减少β-淀粉样蛋白的产生。结论这些结果表明GPR40可能是AD的潜在治疗靶点，GPR40激动剂可能成为未来有前景的AD药物。