目的 探究锁阳醋酸乙酯提取物（ECS）对阿尔茨海默症（AD）模型小鼠行为学、线粒体组织形态学及线粒体动力学相关蛋白表达的影响和作用机制。方法 采用8周龄AD模型5xFAD转基因小鼠为模型组，8周龄野生型C57BL/6小鼠为对照组，ECS组为模型鼠ig ECS 47 mg/kg，每天1次，连续14 d。给药6和12周分别进行跳台、水迷宫、旷场行为学检测；给药12周后取海马部位进行电镜观察；Western blotting检测线粒体融合相关蛋白MFN1、OPA1和线粒体分裂相关蛋白DRP1的表达。结果 水迷宫结果显示，给药6周，3组间均无显著性差异；给药12周后，与对照组比较，模型组小鼠潜伏期时间延长（P<0.05），穿越平台次数显著减少（P<0.05）；与模型组比较，ECS组小鼠潜伏期时间显著缩短（P<0.05），穿越平台次数显著增加（P<0.05）；跳台结果显示，与对照组比较，给药6周及12周，模型组小鼠跳台潜伏期时间显著缩短（P<0.05），跳台次数显著增多（P<0.05）；与模型组比较，给药6周，ECS组无显著性差异；给药12周，ECS组跳台潜伏期时间显著延长（P<0.05），跳台次数显著减少（P<0.05）。旷场结果显示，给药12周，三组均无显著性差异。电镜结果显示，对照组线粒体结构清晰膜完整，嵴排列整齐；模型组线粒体膜破裂、直径变小、嵴扭曲模糊；ECS组线粒体嵴不完全变形，部分基质出现空泡。Western blotting结果显示，与对照组比较，模型组OPA1及MFN1蛋白表达水平显著下调，DRP1蛋白表达水平显著上调（P<0.05）；与模型组比较，ECS组MFN1、OPA1蛋白表达水平显著上调（P<0.05、0.01），DRP1蛋白表达水平显著下调（P<0.05）。结论 ECS显著改善AD模型小鼠的行为学，机制可能与调节线粒体动力学失衡相关。

Objective To investigate the effect and mechanism of the effective fraction of Cynomorium songaricum Ethyl Acetate Extract (ECS) on behavior, mitochondrial histomorphology and expression of mitochondrial kinetic-related proteins in Alzheimer's disease model mice. Methods 8-week-old AD model 5xFAD transgenic mice were used as the model group, 8-week-old wild-type C57BL/6 mice as the control group, and ECS as the administration group. After 6 weeks and 12 weeks of administration, the behaviors of platform jumping, water maze and so on were detected. After 12 weeks of administration, the hippocampus was taken and observed by electron microscope. Western blotting was used to detect the expression of MFN1, OPA1 and DRP1. Results The results of water maze showed that there was no significant difference among the three groups after 6 weeks of administration, but after 12 weeks of administration, the incubation period of the model group was longer than that of the control group (P < 0.05), and the number of crossing the platform was decreased (P < 0.05). Compared with the model group, the latency time and the number of crossing the platform in ECS group were shorter (P < 0.05) and higher than those in model group (P < 0.05). The results of platform jumping showed that compared with the control group, the latency time of platform jump in the model group was shortened (P < 0.05) and the number of platform jumping was increased (P < 0.05), which was similar to that in the model group. After 6 weeks of administration, there was no significant difference in ECS group, but at 12 weeks of administration, the latency time of platform jump in ECS group was prolonged and the number of platform jumping was decreased (P < 0.05). The results of open field showed that there was no significant difference among the three groups at 12 weeks. The results of electron microscope showed that the structure of mitochondria in the control group was clear and the crest was arranged neatly, while in the model group, the mitochondrial membrane ruptured, the diameter became smaller and the cristae were distorted and blurred. Western blotting results showed that compared with the control group, the expression level of OPA1 and mfn1 protein in the model group was significantly down regulated, and the expression level of drp1 protein was significantly up regulated (P < 0.05); compared with the model group, the expression level of mfn1 and OPA1 protein in the ECS group was significantly up regulated (P < 0.05, 0.01), and the expression level of drp1 protein was significantly down regulated (P < 0.05). Conclusion ECS can significantly improve the behavior of AD mice, and the mechanism may be related to the regulation of mitochondrial dynamics imbalance.

R965

北京市自然科学基金（面上项目）（18G40092）