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

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

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Pages (from-to)2079-2088
Number of pages10
JournalNeural Regeneration Research
Volume17
Issue number9
DOIs
StatePublished - Sep 2022

Bibliographical note

Funding Information:
Funding: This study was supported by the National Natural Science Foundation of China 唀 No 堀  縁?o TW 缀 and Natural Science Foundation of Jiangsu 唀 China 唀 No 堀 BK  縁?o QL 缃? How to cite this article: Liu Y唀 Hu PP唀 ?hai S 唀 Feng WX 唀 ?hang R 唀 Li Q唀 Marshall C唀 Xiao M 唀 Wu T 縃缀 Aquaporin  deficiency eliminates the beneficial effects of voluntary exercise in a mouse model of Alzheimer ? s disease 堀 Neural Regen Res 縃缃P 爃堀

Funding Information:
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).

Publisher Copyright:
© 2022 Neural Regeneration Research. All rights reserved.

Keywords

  • Alzheimer's disease
  • amyloid-beta
  • aquaporin-4
  • astrocytes
  • glymphatic system
  • learning and memory
  • synaptic protein
  • transgenic mice
  • voluntary exercise

ASJC Scopus subject areas

  • Developmental Neuroscience

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