Long-term running exercise alleviates cognitive dysfunction in APP/PSEN1 transgenic mice via enhancing brain lysosomal function

Xue Wang1, Yu-ting Zhu1, Yi Zhu1, Yan-ling Sun1, Jun Huang1, Zhe Li1, Yan Wang2, Jun-chao Wu1, Zheng-hong Qin1, Fang Lin1
1 Department of Pharmacology, Laboratory of Aging and Nervous Diseases (SZS0703), Jiangsu Key Laboratory of Neuropsychiatric Disease, College of Pharmaceutical Sciences, Soochow University, Suzhou 215123, China
2 Department of Pediatrics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
Correspondence to: Zheng-hong Qin:, Fang Lin:,
DOI: 10.1038/s41401-021-00720-6
Received: 20 January 2021
Accepted: 17 June 2021
Advance online: 16 July 2021


Amyloid-β peptide (Aβ) aggregation is the hallmark of Alzheimer’s disease (AD). The imbalance between the production and clearance of Aβ results in the accumulation and aggregation of Aβ in the brain. Thus far, few drugs are available for AD treatment, but exercise has been recognized for its cognition-enhancing properties in AD patients. The underlying mechanisms remain unclear. Our recent study showed that long-term running exercise could activate the lysosomal function in the brains of mice. In this study, we investigated whether exercise could reduce Aβ accumulation by activating lysosomal function in APP/PSEN1 transgenic mice. Started at the age of 5 months, the mice were trained with a running wheel at the speed of 18 r/min, 40 min/d, 6 d/week for 5 months, and were killed at the end of the 10th month, then brain tissue was collected for biochemical analyses. The cognitive ability was assessed in the 9th month. We showed that long-term exercise significantly mitigated cognitive dysfunction in AD mice, accompanied by the enhanced lysosomal function and the clearance of Aβ in the brain. Exercise significantly promoted the nuclear translocation of transcription factor EB (TFEB), and increased the interaction between nuclear TFEB with AMPK- mediated acetyl-CoA synthetase 2, thus enhancing transcription of the genes associated with the biogenesis of lysosomes. Exercise also raised the levels of mature cathepsin D and cathepsin L, suggesting that more Aβ peptides could be degraded in the activated lysosomes. This study demonstrates that exercise may improve the cognitive dysfunction of AD by enhancing lysosomal function.
Keywords: Alzheimer’s disease; exercise; Aβ clearance; lysosomal function; TFEB; ACSS2; APP/PSEN1 transgenic mice

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