Beneficial effects of voluntary exercise therapy on an Alzheimer’s mouse model are dependent on aquaporin 4-mediated glymphatic transport

Abstract

Background: Epidemiological and clinical evidence suggest there is an effective time window for the ability of exercise to slow the progression of Alzheimer's disease (AD). Astrocyte aquaporin-4 (AQP4) dependent glymphatic transport is necessary for clearance of extracellular amyloid-β (Aβ) from the brain. The purpose of this study is to explore whether this Aβ clearance mechanism is involved in the time-dependent benefit of exercise on Aβ related pathology. Method: 3- and 7-month-old male wild type (WT) mice, APP695swe/PS1-dE9 (APP/PS1) mice and AQP4 knockout (AQP4−/−)/APP/PS1 mice received voluntary wheel exercise intervention for 2 months, followed by behavioral and pathological analyses.Results: 9-month-old APP/PS1 mice showed enhanced reactive astrogliosis, accompanied with widespread loss of perivascular AQP4 polarization, when compared to 5-month-old APP/PS1 mice. Voluntary exercise improved AQP4 polarity and glymphatic transport, reduced glial inflammation and brain Aβ plaque load, plus alleviated synapse protein loss and cognitive deficits in 5-month-old, but not 9-month-old, APP/PS1 mice. Exercise intervention did not mitigate glymphatic transport dysfunction, Aβ accumulation and cognitive impairment in AQP4−/−/APP/PS1 mice at 5 or 9 months of age. Conclusion: These results have revealed that AQP4-dependent glymphatic transport is an influential factor in the timeliness of voluntary exercise ability to alleviate Aβ pathology, potentially offering a new target for the early prevention of the disease.

Functional aspects of the brain lymphatic drainage system in aging and neurodegenerative diseases

“…Exercise as a healthy lifestyle has been reported to reduce cognitive impairment in patients with dementia [124] . In rodent studies, voluntary exercise increased CSF flow in the brain during the wakefulness of young mice [125] and attenuated amyloid plaque deposition, improved AQP4 polarity distributions and spatial cognitive memory performance of the aged mice [126] . Furthermore, the Aqp4 knockout APP/PS1 mice had more severe deficits in glymphatic transport functions, Aβ plaque deposition, and cognitive impairment, which were not alleviated after the exercise intervention [127] .…”