游泳训练预防阿尔茨海默病的线粒体机制研究

At present, Alzheimer’s disease (AD) has become the most common neurodegenerative diseases in the elderly, with cognitive impairment as the main clinical features. By the time an individual develops symptoms of AD, the patient's brain neurons have already been exposed to years of irreversible damage of Aβ peptide; and the current medication can only partially alleviate AD symptoms, while the improvement is very limited. Therefore, there is an urgent need to explore new cures and mechanisms for AD prevention for the present society. In the progression of AD, Aβ deposition targeting the mitochondria triggers the imbalances of mitochondrial "homeostasis" (features as mitochondrial dysfunction, dynamic imbalance, disorders in mito-biogenesis and distribution, oxidative damage as well as activation of apoptotic pathways), which eventually results in neurodegeneration of the AD brain. Using transgenic AD rats as our research subject, an animal model that can closely mimic human AD in the present, this proposal is designed to investigate the effect of swimming exercise training on AD prevention. Based on our previous studies and preliminary experimental results, we propose that swimming training is able to: 1) protect AD brain neurons and enhance cognitive function; 2) maintain the mitochondrial "healthy status" (enhance cell tolerance, inhibit apoptosis pathway and promote Aβ clearance) and inhibit mitochondrial oxidative stress-induced Aβ deposition. By using a transgenic AD rat model that simulates all the phenotypes of human AD, this proposal is planned to explore, for the first time, the underlying mitochondrial mechanism of swimming exercise training for AD prevention. This project thus has important value for AD prevention.

目前，以认知功能障碍为主要临床特征的阿尔茨海默病(AD)已成为老年人最常见的神经退行性疾病。AD症状出现时，病人脑神经已经受Aβ肽的多年不可逆损害；而当前的药物治疗只能部分缓解其症状，效果十分有限。因此，探寻预防AD的新方法和机制成为当前社会的迫切需要。AD进程中靶向线粒体的Aβ沉积触发了线粒体“稳态”失衡(特征如功能紊乱、动态失衡，再生、分布障碍，氧化损伤和凋亡通路激活)，最终导致神经退行病变。本课题以目前最接近人类AD的转基因大鼠为研究对象，拟探讨游泳训练对AD的预防作用。基于前期研究及预实验结果，申请人提出游泳训练能够：1)保护AD神经元、增强认知功能；2)维持线粒体的“健康态”(增强细胞耐受、抑制凋亡通路、促进Aβ清除)、抑制线粒体氧化应激引起的Aβ沉积。转基因AD大鼠能模拟人类AD的所有表型，本课题以此模型首次探讨游泳训练的线粒体机制，对老龄化社会AD的预防具有重要价值。

阿尔茨海默病是目前最常见的一种神经退行性疾病，也是“痴呆”中最常见的一种。其主要病理特征为学习认知功能障碍、神经元外Aβ聚积形成的老年斑、神经元内tau的过度磷酸化、线粒体功能失调、炎症反应和氧化应激。 虽已有大量靶向AD典型病理特征的相关研究，但大部分在临床转化阶段以失败而告终。此外，目前已有的药物治疗仅能够部分缓解AD症状，效果十分有限。其中一个可能的原因就是AD症状出现时，Aβ聚积和tau的过度磷酸化已经造成神经元的不可逆损伤，提示AD的预防或比治疗更为重要。运动作为一种最常见的非侵入治疗手段对AD的预防作用已有报道，但相关的线粒体机制尚不清楚。..本课题认为AD进程中Aβ沉积触发了线粒体“稳态”失衡（特征如功能紊乱、动态失衡，再生、分布障碍，氧化损伤和凋亡通路激活），最终导致神经退行病变。本课题以目前最接近人类AD的转基因大鼠为研究对象，拟探讨游泳训练对AD的预防的作用和线粒体保护机制。..我们的研究发现游泳训练能够：1) 保护AD神经元、增强认知功能；2）减少AD脑组织中Aβ导致的“老年斑”沉积和tau的过度磷酸化；3）减少线粒体碎片化、减少线粒体细胞色素c氧化酶释放导致的神经元凋亡、保护线粒体功能；4）减少氧化应激和炎症反应。..本课题通过探究短、中、及长期游泳训练对转基因AD大鼠进行干预，阐明了短、中、长期游泳训练对AD转基因大鼠学习和记忆功能、AD典型病理特征及“线粒体健康态”的影响，为运动预防AD提供了新的证据。