Voluntary wheel running did not alter gene expression in 5xFAD mice, but in wild-type animals exclusively after one-day exercise bout. Voluntary wheel running did not alter gene expression in 5xFAD mice, but in wild-type animals exclusively after one-day exercise bout

Physical activity is considered a promising preventive intervention to reduce the risk of developing Alzheimer’s disease (AD). However, the positive effect of exercise therapy has not been proven conclusively yet, likely due to confounding factors such as varying activity regimens and life or disease stages. To examine the impact of different exercise regimens in the early disease stages, we subjected young 5xFAD and wild-type mice to 1-day (acute, 3-month-old) and 30-day (chronic, 2-month-old) voluntary wheel running and compared them with age-matched sedentary controls. We observed a significant increase in brain lactate levels in acutely trained 5xFAD mice relative to all other experimental groups. Subsequent RNA-seq analysis from brain did not reveal major differences in transcriptomic regulation between training durations in 5xFAD mice. In contrast, acute training yielded large gene expression differences in wild-type animals relative to their chronically trained and sedentary counterparts. The comparison of 5xFAD and wild-type mice showed the highest transcriptional differences in the chronic and sedentary groups, whereas acute training was associated with much fewer DEGs. In conclusion, our results suggest that different training durations did not affect the global transcriptome of 3-month-old 5xFAD mice, whereas acute running seemed to induce a similar transcriptional stress state in wild-type animals as already known for 5xFAD mice. Overall design: Brain mRNA profiles of 3-month-old wild type (WT) and 5xFAD male mice after three different training levels

体力活动被认为是一种颇具前景的预防性干预手段，可降低阿尔茨海默病（Alzheimer’s disease, AD）的发病风险。然而，运动疗法的积极效应尚未得到确凿证实，这可能源于混杂因素的影响，例如运动方案的差异以及个体所处的生命阶段或疾病进程阶段。为探究不同运动方案在疾病早期阶段的影响，我们将年轻的5xFAD小鼠与野生型（wild-type）小鼠分别施以1天（急性运动，受试时月龄为3个月）和30天（慢性运动，受试时月龄为2个月）的自愿转轮运动，并与同年龄段的静息对照组进行比较。我们观察到，相较于其余所有实验组，急性运动组的5xFAD小鼠脑内乳酸水平显著升高。后续对脑组织进行的RNA测序（RNA-seq）分析未发现5xFAD小鼠在不同运动时长下的转录组调控存在显著差异。与之相反，急性运动使野生型小鼠的基因表达出现大幅差异，这一结果与慢性运动组及静息对照组的野生型小鼠形成鲜明对比。对5xFAD与野生型小鼠的比较显示，慢性运动组与静息组的转录组差异最为显著，而急性运动组的差异表达基因（differentially expressed genes, DEGs）数量则少得多。综上，我们的研究结果表明，不同运动时长并未对3月龄5xFAD小鼠的整体转录组产生影响，而急性转轮运动似乎可在野生型小鼠中诱导出与已知5xFAD小鼠类似的转录应激状态。整体实验设计：对三种不同运动干预模式下的3月龄雄性野生型（wild-type, WT）与5xFAD小鼠的脑组织mRNA谱进行分析。