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.

Yun Liu;Pan-Pan Hu;Shuang Zhai;Wei-Xi Feng;Rui Zhang;Qian Li;Charles Marshall;Ming Xiao;Ting Wu

Department of Neurology,the First Affiliated Hospital of Nanjing Medical University,Nanjing,Jiangsu Province,China;Jiangsu Province Key Laboratory of Neurodegeneration,Nanjing Medical University,Nanjing,Jiangsu Province,China;Brain Institute,the Affiliated Nanjing Brain Hospital of Nanjing Medical University,Nanjing,Jiangsu Province,China;College of Health Sciences,University of Kentucky Center of Excellence in Rural Health,Hazard,KY,USA

中国神经再生研究（英文版）

[1]Yun Liu;Pan-Pan Hu;Shuang Zhai;Wei-Xi Feng;Rui Zhang;Qian Li;Charles Marshall;Ming Xiao;Ting Wu-.Aquaporin 4 deficiency eliminates the beneficial effects of voluntary exercise in a mouse model of Alzheimer's disease)[J].中国神经再生研究（英文版）,2022(09):2079-2088

paravascular,glymphatic,mislocalization

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