运动干预调控海马神经元自噬改善阿尔茨海默病模型小鼠学习记忆障碍

Exercise intervention alleviating learning and memory dysfunction of Alzheimer's disease model mice through modulating autophagy of hippocampal neurons

目的探讨8周规律运动干预对阿尔茨海默病(AD)模型小鼠海马神经元自噬水平及其学习记忆障碍的影响。方法4月龄雄性APP/PS1 AD模型鼠随机分为AD模型安静组(AS)和AD模型运动组(AE),同月龄C57BL/6小鼠作为正常对照组(CS),每组均为12只。其中,AE组小鼠进行8周规律跑台运动,5 d/周,60 min/d。前10 min运动速度为10 m/min,后50 min为12 m/min,跑台坡度均为0°。Morris水迷宫实验、新奇物识别测试、免疫组织化学、Western blotting、透射电子显微镜和尼氏染色检测各组小鼠的学习记忆能力,β-淀粉样蛋白(Aβ)、人微管相关蛋白轻链3B(LC3B)、Beclin1和p62的蛋白表达水平,以及自噬体、自噬溶酶体和神经元的数量。结果6月龄时AD模型小鼠呈现出学习记忆障碍。而8周运动干预可显著的改善AD模型小鼠在Morris水迷宫实验和新奇物识别测试中的学习记忆水平。AS组小鼠海马区Aβ斑块和p62蛋白表达水平显著提高,而LC3B、Beclin1、自噬溶酶体和神经元数量显著降低。运动干预显著降低AD模型小鼠海马区Aβ斑块和p62蛋白表达水平,并提高LC3B、Beclin1、自噬溶酶体和神经元数量。结论运动干预可有效改善AD模型小鼠海马神经元自噬的损伤,促进自噬溶酶体降解病理性Aβ以保护海马神经元,进而改善AD模型小鼠学习记忆能力。

Objective To investigate the effects of exercise on autophagy of the hippocampal neurons and learning and memory abilities in APP/PS1 transgenic Alzheimer's disease(AD)model mice.MethodsFour-month-old male APP/PS1 mice were randomly divided into AD model sedentary group(AS)and AD model exercise group(AE).C57BL/6 mice of the same age were used as control group(CS),with 12 mice in each group.Among them,AE group mice underwent regular treadmill exercise at 10 m per minute(the first 10 minutes)and 12 m per minute(the following 50 minutes)for 60 min,0°slope,5 days/week,for 8 weeks.Morris water maze,novel object recognition test,immunohistochemistry,Western blotting,transmission electron microscopy,and Nissl staining were used to detect learning memory abilities,amyloidβ-protein(Aβ),human microtubule-associated protein light chain 3B(LC3B),Beclinl,p62 protein expression,autophagy lysosomes and neuron number.Results Eight weeks of exercise intervention could significantly improve the learning and memory abilities of AD model mice in the Morris water maze and novel object recognition test.The expression levels of Aβplaques and p62 protein in the hippocampus of mice in the AS group increased significantly,while the levels of LC3B,Beclinl,autophagy lysosomes and neurons decreased significantly.Exercise intervention significantly reduced the expression levels of Aβplaques and p62 protein in the hippocampus of AD model mice,and increased the levels of LC3B,Beclinl,autophagolysosomes and neurons.Conclusion Exercise could effectively improve the damage of neuronal autophagy in the hippocampus of AD model mice and protect the neurons through promoting autophagy lysosomes to degrade pathological Ap in the hippocampus.These result might underlie the mechanisms for the treadmill exercise-induced improvement of learning and memory abilities.