运动通过Parkin调控老年海马神经元线粒体自噬和认知功能的机制

Exercise can ameliorate the age-related cognitive decline, however the underlying mechanism has not been fully elucidated. Autophagy and mitochondrial dysfunction play important roles in age-related cognitive decline, however Parkin-mediated mitophagy during aging and its relation with cognitive function are still not clear. Our previous study has revealed that exercise can improve mitochondrial quality control and thus ameliorate age-related cognitive decline through activation of autophagy/mitophagy signaling; meanwhile, exercise can upregulate Parkin expression in aged hippocampus. We proposed that exercise can improve cognitive function by activation of Parkin-mediated mitophagy in aged hippocampus. This study aims that: 1. elucidate the alteration of Parkin-mediated mitophagy in aged hippocampus and its relation with cognitive function; 2. reveal the mechanism that exercise modulates Parkin-mediated mitophagy and cognitive function using tools including genetically engineered mouse strain and ShRNA. This study has the potential to confirm a new mechanism of the neuroprotective effects of exercise, and provide sufficient scientific evidence for the establishment of Parkin as a target for the treatment of neurodegenerative diseases, and also prevention of brain aging through proper exercise training.

运动能延缓老年认知功能减退，但其机制仍远未阐明。已知自噬和线粒体功能障碍是老年认知功能减退的重要原因。Parkin是调控线粒体自噬，维持线粒体稳态的关键蛋白之一，但衰老过程中海马神经元Parkin介导的线粒体自噬的改变及其与认知功能的关系仍不清楚。我们前期发现，运动能通过激活老年海马神经元自噬/线粒体自噬，改善线粒体质量控制，增强认知功能；同时，运动能上调Parkin表达。据此我们提出，运动能通过Parkin激活老年海马神经元线粒体自噬，改善认知功能。本项目旨在：1. 阐明老年海马神经元Parkin介导的线粒体自噬的改变及其与认知功能的关系；2. 采用基因工程小鼠、ShRNA等工具，揭示运动通过Parkin调控老年海马神经元线粒体自噬和认知功能的机制。本项目有望揭示运动神经保护作用的新机制，为确立Parkin作为神经退行性疾病治疗的靶点和老年人科学运动预防脑衰老提供更充分的科学依据。

运动能延缓老年认知功能减退，但其机制仍远未阐明。已知自噬和线粒体功能障碍是老年 认知功能减退的重要原因。我们前期发现，运动能通过激活老年海马神经元自噬/线粒体自噬，改善线粒体质量控制，增强认知功能；同时，运动能上调Parkin表达。据此我们提出，运动能通过Parkin激活老年海马神经元线粒体自噬，改善认知功能。本课题取得如下研究成果：①阐明不同方式运动对中年、老年小鼠海马Parkin介导的线粒体自噬、线粒体质量控制和认知功能的影响；②发现AMPK在运动调控老年海马Parkin介导的线粒体自噬和线粒体质量控制中起关键作用；③探讨运动对脂多糖诱导的老年小鼠认知功能减退和神经炎症的影响，发现Parkin介导的线粒体自噬是运动发挥保护作用，减轻神经炎症的可能机制。本项目揭示了运动神经保护作用的新机制，为老年人通过合理运动预防、干预脑衰老提供了更充分的科学依据。