中国神经再生研究(英文版) ›› 2022, Vol. 17 ›› Issue (9): 2079-2088.doi: 10.4103/1673-5374.335169

• 原著:退行性病与再生 • 上一篇    

水通道蛋白 4 缺失可抵消自主运动对阿尔茨海默病模型的有益影响

  

  • 出版日期:2022-09-15 发布日期:2022-03-08

Aquaporin 4 deficiency eliminates the beneficial effects of voluntary exercise in a mouse model of Alzheimer’s disease

Yun Liu1, Pan-Pan Hu2, 3, Shuang Zhai1, Wei-Xi Feng2, 3, Rui Zhang1, Qian Li1, Charles Marshall4, Ming Xiao2, 3, *, Ting Wu1, *   

  1. 1Department of Neurology, the First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu Province, China; 2Jiangsu Province Key Laboratory of Neurodegeneration, Nanjing Medical University, Nanjing, Jiangsu Province, China; 3Brain Institute, the Affiliated Nanjing Brain Hospital of Nanjing Medical University, Nanjing, Jiangsu Province, China; 4College of Health Sciences, University of Kentucky Center of Excellence in Rural Health, Hazard, KY, USA
  • Online:2022-09-15 Published:2022-03-08
  • Contact: Ming Xiao, MD, PhD, mingx@njmu.edu.cn; Ting Wu, MD, PhD, wuting@njmu.edu.cn.
  • Supported by:
    This study was supported by the National Natural Science Foundation of China, No. 81772454 (to TW) and Natural Science Foundation of Jiangsu, China, No. BK20190655 (to QL).

摘要:

长期规律运动已被证明可降低阿尔茨海默病的风险。作者前期研究已发现特异性表达于星形胶质血管旁突起上的水通道蛋白4是胶质淋巴清除的关键功能蛋白,具有延缓阿尔茨海默病进程的作用。但是水通道蛋白4调控的胶质淋巴清除功能是否参与运动治疗阿尔茨海默病具有时效性尚不可知。此次实验发现3月龄APP/PS1小鼠进行为期2个月的自主运动后,其大脑Aβ负荷、神经胶质激活、血管周围水通道蛋白4 错误定位、胶质淋巴运输损伤、突触蛋白丢失以及学习和记忆障碍均明显减轻;而水通道蛋白4极性和胶质淋巴转运功能已明显损伤的7月龄APP/PS1小鼠经2个月的自主运动后上述指标没有明显变化。与年龄匹配的APP/PS1相比,AQP4基因敲除的APP/PS1小鼠存在更严重的胶质淋巴功能损害、Aβ斑块沉积和认知障碍,且运动干预后无改善。提示水通道蛋白4胶质淋巴清除功能是运动延缓阿尔茨海默病发生的神经生物学基础。

https://orcid.org/0000-0001-5528-9102 (Ming Xiao)

关键词: 阿尔茨海默病, β淀粉样蛋白, 星形胶质细胞, 水通道蛋白4, 胶质淋巴系统, 学习记忆, 突触蛋白, 转基因小鼠, 自主运动

Abstract: Regular exercise has been shown to reduce the risk of Alzheimer’s disease (AD). Our previous study showed that the protein aquaporin 4 (AQP4), which is specifically expressed on the paravascular processes of astrocytes, is necessary for glymphatic clearance of extracellular amyloid beta (Aβ) from the brain, which can delay the progression of Alzheimer’s disease. However, it is not known whether AQP4-regulated glymphatic clearance of extracellular Aβ is involved in beneficial effects of exercise in AD patients. Our results showed that after 2 months of voluntary wheel exercise, APP/PS1 mice that were 3 months old at the start of the intervention exhibited a decrease in Aβ burden, glial activation, perivascular AQP4 mislocalization, impaired glymphatic transport, synapse protein loss, and learning and memory defects compared with mice not subjected to the exercise intervention. In contrast, APP/PS1 mice that were 7 months old at the start of the intervention exhibited impaired AQP4 polarity and reduced glymphatic clearance of extracellular Aβ, and the above-mentioned impairments were not alleviated after the 2-month exercise intervention. Compared with age-matched APP/PS1 mice, AQP4 knockout APP/PS1 mice had more serious defects in glymphatic function, Aβ plaque deposition, and cognitive impairment, which could not be alleviated after the exercise intervention. These findings suggest that AQP4-dependent glymphatic transport is the neurobiological basis for the beneficial effects of voluntary exercises that protect against the onset of AD. 

Key words: Alzheimer’s disease, amyloid-beta, astrocytes, aquaporin-4, glymphatic system, learning and memory, synaptic protein, transgenic mice, voluntary exercise