Voluntary Wheel Running Reduces Amyloid-β42 and Rescues Behavior in Aged Tg2576 Mouse Model of Alzheimer’s Disease

Francis, Nikita; Robison, Lisa S.; Popescu, Dominique; Michaelos, Michalis; Hatfield, Joshua; Xu, Feng; Zhu, Xiaoyue; Davis, James Earl; Anderson, Monica; Anderson, Brenda J.; Nostrand, William E. Van; Robinson, John K.

doi:10.3233/jad-190810

Cited by 8 publications

(1 citation statement)

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“…Experimental animal studies indicate that exercise plays a variety of neuroprotective roles, including promoting neurogenesis, reducing neuroin ammation, improving mitochondrial energy metabolism and promoting neurotrophic factor secretion [12,13]. Notably, both voluntary exercise and forced exercise have been shown to reduce extracellular Aβ levels in the brains of several transgenic mouse models of AD [14][15][16][17]. However, there is considerable evidence that exercise interventions do not reduce Aβ plague load in mice with mid-to late-stage AD-like pathology [18][19][20][21].…”

Section: Introductionmentioning

confidence: 99%

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

Liu

Feng

et al. 2020

Preprint

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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.

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