Jiao Juan-Juan, Hölscher Christian, Li Tian, Dong Xue-Fan, Qu Xue-Song, Cao Yue, Wu Mei-Na, Wang Zhao-Jun, Qi Jin-Shun
Department of Physiology, Key Laboratory for Cellular Physiology of Ministry of Education, Shanxi Medical University, Taiyuan 030001, China.
Division of Biomedical and Life Sciences, Faculty of Health and Medicine, Lancaster University, Lancaster LA1 4YQ, UK.
Sheng Li Xue Bao. 2017 Apr 25;69(2):135-145.
Alzheimer's disease (AD) is a progressively neurodegenerative disorder, which seriously affects human health but is still irreversible up to now. Recent studies indicate that type 2 diabetes mellitus (T2DM) is an important risk factor for AD, and the drugs used for treatment of T2DM have shown some neuroprotective effects in the treatment of AD. Glucagon-like peptide-1 (GLP-1)/ glucose-dependent insulinotropic polypeptide (GIP)/glucagon (Gcg) receptor Triagonist is a new monomeric polypeptide equally activating the GLP-1/GIP/Gcg receptors, which is built on the basis of GLP-1/Gcg receptor coagonist core sequence, and incorporated with partial amino acids of GIP. Recently, the Triagonist has been reported to be effective in alleviating diabetic complications in rodent models of obesity. The present study observed for the first time the cognitive improvement effects of the Triagonist in the triple-transgenic AD mice (3xTg-AD) by using multiple behavioral techniques, and explored its probable molecular mechanisms using ELISA and Western blot. The results showed that the chronic treatment with the Triagonist (i.p.) significantly reversed the impairments in working memory of 3xTg-AD mice, with an obvious increase in the percentage of correct spontaneous alternation in the Y maze; the Triagonist treatment also improved long-term spatial memory and re-learning ability of 3xTg-AD mice in classical Morris water maze and reverse water maze tests, with decreased escape latency in under water platform tests and increased swimming time in probe tests. ELISA and Western blot experiments showed that the Triagonist up-regulated the levels of cAMP, PKA and p-CREB in the hippocampus of 3xTg-AD mice. These results indicate that GLP-1/GIP/Gcg receptor Triagonist can improve the cognitive behaviors in 3xTg-AD mice, and the up-regulation of hippocampal cAMP/PKA/CREB signal pathway may mediate the neuroprotection of the Triagonist, suggesting that the GLP-1/GIP/Gcg receptor Triagonist may be a novel therapeutic strategy for the treatment of AD.
阿尔茨海默病（AD）是一种进行性神经退行性疾病，严重影响人类健康，但至今仍不可逆转。最近的研究表明，2型糖尿病（T2DM）是AD的一个重要危险因素，用于治疗T2DM的药物在AD治疗中已显示出一些神经保护作用。胰高血糖素样肽-1（GLP-1）/葡萄糖依赖性促胰岛素多肽（GIP）/胰高血糖素（Gcg）受体三联激动剂是一种新的单体多肽，可同等程度地激活GLP-1/GIP/Gcg受体，它基于GLP-1/Gcg受体共激动剂核心序列构建，并掺入了GIP的部分氨基酸。最近，有报道称三联激动剂在肥胖啮齿动物模型中可有效减轻糖尿病并发症。本研究首次使用多种行为学技术观察了三联激动剂对三转基因AD小鼠（3xTg-AD）认知功能改善的作用，并使用酶联免疫吸附测定（ELISA）和蛋白质免疫印迹法（Western blot）探讨了其可能的分子机制。结果显示，三联激动剂腹腔注射长期治疗可显著逆转3xTg-AD小鼠工作记忆的损伤，Y迷宫中正确自发交替的百分比明显增加；三联激动剂治疗还改善了3xTg-AD小鼠在经典莫里斯水迷宫和反向水迷宫试验中的长期空间记忆和重新学习能力，水下平台试验中的逃避潜伏期缩短，探针试验中的游泳时间增加。ELISA和Western blot实验表明，三联激动剂上调了3xTg-AD小鼠海马中cAMP、蛋白激酶A（PKA）和磷酸化环磷腺苷反应元件结合蛋白（p-CREB）的水平。这些结果表明，GLP-1/GIP/Gcg受体三联激动剂可改善3xTg-AD小鼠的认知行为，海马cAMP/PKA/CREB信号通路的上调可能介导了三联激动剂的神经保护作用，提示GLP-1/GIP/Gcg受体三联激动剂可能是治疗AD的一种新策略。
