Cognitive–Exercise Dual-Task Intervention Ameliorates Cognitive Decline in Natural Aging Rats via Regulating lncRNA NEAT1/miR-124-3p/caveolin-1-PI3K/Akt/GSK3β Pathway

Abstract Background: Aging induces degenerative changes in the body and causes cognitive dysfunction, which has a significant negative impact on the daily lives of older adults. At present, there are limited effective interventions to slow the incidence of Aging-related cognitive impairment or even dementia. Among them, exercise and cognitive training are worthy of further research, especially the research on mechanisms. Studies have shown that LncRNA and miRNA play an important role in the occurrence, development, and rehabilitation of aging-related cognitive impairment. We aimed to identify the effect of cognitive-exercise dual-task training on cognitive function in naturally aged rats and to investigate the mechanism by which the LncRNA NEAT1/miR124-3p/caveolin-1-PI3K/Akt/GSK3β pathway plays a role in the improvement of cognitive function with dual-task training. Methods: Forty SD rats at 18 months of age were randomly divided into four groups (n=10 for each group): exercise training group, cognitive training group, cognitive-exercise dual-task training group, and aging control group. Each group underwent 12 weeks of intervention according to their corresponding training protocols. New object recognition tests were performed on all rats after the completion of the intervention. The expressions of related pathway proteins, LncRNA, and miRNA in the hippocampus were examined by Western blotting (WB) and/or Quantitative real-time polymerase chain reactions (qRT-PCR) after euthanasia of the rats. HT22 mouse hippocampal neuronal cells were cultured and miR-124-3p and lncRNA NEAT1 were over-expressed/down-expressed, respectively. WB and/or qRT-PCR were used to determine the levels of caveolin-1-PI3K/Akt/GSK3 pathway, miR-124-3p, and lncRNA NEAT1 expression in the neurons. Results: The results showed that compared with the aging control group, the cognitive-exercise dual-task training group had better performance on novelty recognition (P < 0.01), and their expressions of lncRNA NEAT1, caveolin-1, and p-GSK3β were significantly decreased (P < 0.05), while miR124-3p, p-PI3K, and p-Akt were significantly increased (P < 0.05). Conclusion: Our study showed that cognitive-exercise dual-task training improved cognitive function in aging rats better than no training or single training. The mechanism of cognitive function improvement could be related to the regulation of LncRNA NEAT1/miR124-3p- caveolin1/PI3K/Akt/GSK3β pathway.