胰岛素对AD样小鼠学习记忆的影响及其机制

【摘要】目的 研究胰岛素对阿尔茨海默病（AD）样小鼠学习记忆能力的影响及其机制。方法 将21只小鼠随机分为对照(CON) 组、模型（链脲佐菌素，STZ）组和胰岛素治疗(INS) 组，每组7只，后2组小鼠脑室内注射STZ建立 AD模型，INS组小鼠皮下注射胰岛素持续30 d。Morris水迷宫检测小鼠学习记忆能力，Western blotting检测Tau和神经丝（NFs）蛋白的磷酸化水平，荧光染料Fluoro-Jade B（FJB）标记退化神经元。结果 与CON组相比，STZ组小鼠平均逃避潜伏期和路径长度明显增加(P < 0.05)、穿越隐匿平台次数明显减少(P < 0.05)，小鼠脑内Tau蛋白在Ser199/ 202、Ser396/404、Thr212和Thr205位点的磷酸化水平以及NFs蛋白的磷酸化增加(P < 0.05)，FJB标记的小鼠海马CA1 区平均累积光密度(IOD)较CON组明显增加(P < 0.001)；与STZ组相比，INS组小鼠学习记忆改善，逃避潜伏期和路径长度明显减少(P < 0.05)、穿越隐匿平台次数明显增加(P < 0.05)，Tau蛋白特异性位点和NFs蛋白的磷酸化作用明显降低(P < 0.05)，FJB标记的小鼠海马CA1区平均累积分光密度(IOD)明显减少(P < 0.001)。结论 胰岛素能改善STZ脑室内注射的AD样小鼠学习记忆减退，可能与降低Tau和NFs蛋白的过度磷酸化和神经细胞退行性变有关。

The impact of insulin on learning and memory of Alzheimer-like mice and its mechanism

Abstract] Objective To investigate the impact and mechanism of insulin on learning and memory of Alzheimer (AD)-like mice induced by streptozotocin (STZ) intracerebroventricular (i.c.v.) injection. Methods Twenty-one mice were randomly divided into three groups, seven mice in each group: control group (CON), the model group (STZ) and insulin (INS) treatment group. STZ i.c.v. injection was used to establish AD mouse model in the latter two groups. The subcutaneous injection of insulin was administered for 30 days to INS group. Morris water maze was applied to detect the learning and memory ability of mice and Western blotting to analyze the levels of phosphorylated Tau and neurofilament (NFs) proteins. Fluoro-Jade B (FJB) was used to label the degenerative neurons. Results Compared with CON group, the escape latency and path length were increased in STZ group (P < 0.05) with fewer number of crossing hidden platform than that of CON group (P < 0.05). The phosphorylation levels in sites of Ser199/202, Ser396/404, Thr212 and Thr205 of Tau protein and NFs protein phosphorylation were increased in STZ group compared with those of CON group (P < 0.05). The number of FJB-positive neurons was much more in STZ group than that in CON group (P < 0.001). Ccompared with STZ group, the learning and memory were improved, the escape latency and path length were decreased in INS group (P < 0.05). There was a larger number of crossing hidden platform in INS group than that of STZ group (P < 0.05). The phosphorylation levels of Tau in different sites and NFs protein phosphorylation were significantly decreased in INS group than those of STZ group (P < 0.05). The mean integrated optical density of FJB-positive neurons was much fewer in mouse hippocampus in INS group than that of STZ group (P < 0.001). Conclusion Insulin could protect learning and memory function of AD-like mice induced by STZ i.c.v. injection, which may be related to the decrease of the hyperphosphorylation of Tau and NFs proteins, and may be related to the reduction of the neural degeneration.