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

Amyloid-beta peptide (A beta) aggregation is the hallmark of Alzheimer's disease (AD). The imbalance between the production and clearance of A beta results in the accumulation and aggregation of A beta 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 A beta 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 A beta 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 A beta peptides could be degraded in the activated lysosomes. This study demonstrates that exercise may improve the cognitive dysfunction of AD by enhancing lysosomal function.

Automated summary

This study demonstrates that long-term running exercise can significantly alleviate cognitive dysfunction in AD mice by enhancing lysosomal function and promoting the clearance of A beta in the brain. Exercise promotes the nuclear translocation of TFEB and increases the interaction between nuclear TFEB and AMPK-mediated acetyl-CoA synthetase 2, enhancing the transcription of genes associated with lysosomal biogenesis. It also leads to increased levels of mature cathepsin D and cathepsin L, suggesting enhanced degradation of A beta peptides in activated lysosomes.