AQP4调节的胶质淋巴清除功能在有氧运动延缓阿尔兹海默病进程中的作用

There is so far lack of effective drug therapy for Alzheimer's disease (AD). Thus, exploring new non-pharmacological strategies including aerobic exercise against AD and revealing their neuroprotective mechanisms are essential. Numerous studies, including our previous team, showed that the beneficial efficiency of aerobic exercise in the prevention and treatment of AD is timeliness, but its mechanism is not clear. Recently, we found that the water channel protein aquaporin 4 (AQP4) mediated glymphatic system clearing interstitial β-amyloid from the brain, and aerobic exercise can increase the polarity of AQP4 expression. Based on this, we hypothesized that clearance function of the lymphatic system regulated by AQP4 is a key factor in determining the timeliness of aerobic exercise in AD treatment. In order to verify this hypothesis, by using APP/PS1 and the, AQP4 gene knock out in APP/PS1 mice and AQP4 over-expression in APP/PS1 mice at different months, we will clarify whether aerobic exercise promotes the clearance function of glymphatic system, and thus delaying the occurrence and development of AD. The correlation between the timeliness of aerobic exercise in the treatment of AD and the polarity of AQP4 expression will also be addressed. The results is important for elucidating the mechanisms that the integrity of glymphatic system is a basis for aerobic exercise playing protective roles on brain function, but also help to establish a new strategy for treatment of AD via regulation of glymphatic clearance function by targeting at AQP4.

阿尔兹茨海默病(AD)迄今缺乏有效的治疗药物，探索包括有氧运动在内非药物防治AD新方法，并揭示其神经保护机理至关重要。包括本研究团队在内的前期研究结果表明有氧运动对AD防治具有时效性，但其机制不清。我们近期发现水通道蛋白4(AQP4)介导胶质淋巴清除Aβ功能，有氧运动能上调AQP4的表达极性。为此，我们推测AQP4调控的胶质淋巴系统清除功能是决定有氧运动治疗AD具有时效性的关键因素。为了验证此推测，我们拟通过运用不同月龄APP/PS1小鼠和、AQP4基因敲除/APP/PS1小鼠及AQP4过表达/APP/PS1小鼠系统研究有氧运动是否促进胶质淋巴系统清除功能，进而发挥延缓AD发生发展，并明确有氧运动治疗AD的时效性是否与AQP4的表达极性相关。研究结果对阐明脑胶质淋巴系统的完整性是有氧运动发挥脑保护的基础具有重要意义，并为靶向AQP4调控胶质淋巴清除功能治疗AD提供新思路。

研究目的：流行病学和临床证据表明，运动干预对减缓阿尔兹海默氏病（Alzheimer’s disease，AD）的进程具有时效性。依赖于星形胶质细胞上的水通道蛋白-4（Aquaporin4,AQP4）的胶质淋巴运输功能介导了大脑清除细胞外淀粉样蛋白（Aβ）。本研究探讨AQP4介导的胶质淋巴系转运是否参与AD小鼠自主运动的时效性治疗。.研究方法：本实验采用了3月龄、7月龄的APP/PS1小鼠，AQP4基因敲除的APP/PS1(AQP4-/-APP/PS1)小鼠以及野生型（wild type,WT）小鼠进行8周的自主转轮运动，之后进行行为学测试、病理分析。.结果：与5月龄APP/PS1小鼠相比，9月龄APP/PS1小鼠表现出明显的反应性星形胶质细胞增生，并伴有血管旁AQP4的极性的广泛丢失。自主运动干预可以明显改善5月龄而非9月龄APP/PS1小鼠AQP4表达极性、胶质淋巴清除功能、神经炎症反应、淀粉样斑块的积聚，进而缓解了其学习记忆能力损伤。另外，自主运动干预不能缓解5月龄和9月龄AQP4-/-APP/PS1小鼠脑内淀粉样斑块的积聚和空间学习记忆能力缺失。