有氧运动改善AD模型APP/PS1双转基因小鼠中枢神经元线粒体融合分裂动态平衡

线粒体融合分裂平衡是线粒体动力学的需要。本研究观察12周规律有氧运动对APP/PS1双转基因小鼠中枢神经元线粒体融合分裂动态平衡的影响。本研究采用3月龄雄性APP/PS1小鼠（AD模型）随机分为AD安静组（AS）、AD运动组（AE），同月龄雄性C57BL/6J小鼠做正常对照组（CS）。AE组进行12周规律跑台运动，5 d/周，60 min/d。前10 min运动速度12 m/min，后50 min运动速度15 m/min，跑台坡度为0°。八臂迷宫实验检测小鼠工作记忆错误频率和参考记忆错误频率；Western印迹检测小鼠皮层、海马组织中线粒体分裂蛋白Drp1和Fis1的含量，以及Drp1的活性（p-Drp1-Ser616）、线粒体融合蛋白Mfn1、Mfn2、Opa1的表达水平；透射电镜观察皮层、海马线粒体形态结构、健康线粒体比率及线粒体平均直径。本研究证实AS组较CS组工作记忆错误频率显著提高（P<0.05），12周有氧运动显著降低工作记忆错误频率（P<0.05）。AS组小鼠皮层Fis1蛋白和海马脑区Drp1、Fis1蛋白表达水平及皮层、海马脑区Drp1蛋白的活性增加（P<0.05）。而皮层Mfn1和海马Mfn1、Mfn2蛋白表达水平显著降低（P<0.05）。12周有氧运动显著减低Fis1、Drp1蛋白表达及Drp1蛋白的活性，提高Mfn1、Mfn2蛋白表达水平（P<0.05）。AS组小鼠皮层、海马线粒体多呈现球形，部分线粒体膜结构消失，线粒体嵴结构紊乱。且AS组较CS组小鼠健康线粒体比率降低、直径缩短。12周规律有氧运动可明显改善线粒体形态和结构，提高健康线粒体比率及直径。本研究提示，12周规律有氧运动可有效抑制皮层、海马脑区线粒体分裂蛋白Drp1和 Fis1的表达，降低Drp1的活性（p-Drp1-Ser616），上调线粒体融合蛋白Mfn1、Mfn2的蛋白表达水平，改善线粒体形态和结构以促进线粒体质量控制，是有氧运动改善AD模型空间学习记忆能力的分子机制之一。

Aerobic Exercise Regulates Mitochondrial Dynamics-mitochondrial Fission And Fusion In APP/PS1 Transgenic Mice

Mitochondrial dynamics, including mitochondrial fusion and fission balance, is essential for the mitochondria quality control. This study observed the effects of 12 weeks aerobic exercise on mitochondrial dynamics in 6-month-old APP/PS1 transgenic mice. C57BL/6 J mice (3-month-old) and APP/PS1 transgenic mice (3-month-old) were randomly divided into sedentary (CS, AS) and 12 weeks exercise (AE), respectively. The mice in AE group underwent treadmill at 12 m/min (the first 10 min) or 15 m/min (the following 50 min) for 60 min, 0° slope, 5 d/week, for 12 weeks. The behavioral changes were detected by eight arm experiments to observe the frequency of errors of working memory and reference memory. The protein levels of dynamin-related protein (Drp1), p-Drp1-Ser616, fission 1 protein (Fis1), mitofusin 1 (Mfn1), mitofusin 2 (Mfn2), and optic atrophy 1 (Opa1) were measured using Western blotting. The mitochondrial morphology, ratio of healthy mitochondrial and average mitochondrial diameter in the brain tissues were detected by transmission electron microscope. Behaviorally: there was significant changes in 6-month-old AS compared with the control cohorts (CS) in the frequency of working memory errors (P<0.05). The AE mice performed significantly better than those of AS in the frequency of working memory errors (P<0.05). The mice of 6 month-old APP/PS1 group displayed a prominent increase in the protein levels of Fis1 in the cortex, and in the hippocampus compared with the CS controls (P<0.05). Increase of protein levels and activity of Drp1 (p-Drp1-Ser616) was detected in hippocampus. A decrease of protein levels of Mfn1 in the cortex, and Mfn1 and Mfn2 in the hippocampus was also found. Aerobic exercise decreased the expression of Drp1 and Fis1 reduced the activity of Drp1 and increased Mfn1 and Mfn2 protein expression in APP/PS1 mice (P<0.05). The results of transmission electron showed that the ratio of healthy mitochondrial and average mitochondrial diameter decreased in 6-month-old APP /PS1 mice. Swollen mitochondria and ruptured membranes were also observed. The 12 weeks aerobic exercise increased the ratio of healthy mitochondria and average mitochondrial diameter and improved the mitochondrial structure and function. The results suggest that the 12 weeks aerobic exercise can regulate the mitochondrial structure and function of APP/PS1 mice by significantly reducing the expression of Drp1 and Fis1, and the activity of Drp1, and increasing the expression of Mfn1 and Mfn2. Our study may provide information in understating the molecular mechanism of exercise-induced spatial learning and memory ability.