Elevated brain activation, or hyperexcitability, induces cognitive impairment and confers an increased risk of Alzheimer’s disease (AD). Blocking the overexcitation of the neural network may be a promising new strategy to prevent, halt, and even reverse this condition. Physical exercise has been shown to be an effective cognitive enhancer that reduces the risk of AD in elderly individuals, but the underlying mechanisms are far from being fully understood. We explored whether long-term treadmill exercise attenuates amyloid precursor protein (APP)/presenilin-1 (PS1) mutation-induced aberrant network activity and thus improves cognition by altering the numbers and/or distribution of voltage-gated sodium channels (Nav) in transgenic mice. APP/PS1 mice aged 2, 3.5, 5, 6.5, 8, and 9 months underwent treadmill exercise with different durations or at different stages of AD. The alterations in memory, electroencephalogram (EEG) recordings, and expression levels and distributions of Nav functional members (Nav1.1α, Nav1.2, Nav1.6, and Navβ2) were evaluated. The results revealed that treadmill exercise with 12- and 24-week durations 1) induced significant improvement in novel object recognition (NOR) memory and Morris water maze (MWM) spatial memory; 2) partially reduced abnormal spike activity; and 3) redressed the disturbed cellular distribution of Nav1.1α, aberrant Navβ2 cleavage augmentation, and Nav1.6 upregulation. Additionally, APP/PS1 mice in the 24-week exercise group showed better performance in the NOR task and a large decrease in Nav1.6 expression, which was close to the wild-type level. This study suggests that exercise improves cognition and neural activity by altering the numbers and distribution of hippocampal Nav in APP/PS1 mice. Long-term treadmill exercise, for about 24 weeks, starting in the preclinical stage, is a promising therapeutic strategy for preventing AD and halting its progress.

中文翻译：

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运动引起的认知改善与APP / PS1小鼠中钠通道介导的兴奋性有关。

高水平的大脑激活或过度兴奋会引起认知障碍，并增加患阿尔茨海默氏病（AD）的风险。阻止神经网络的过度励磁可能是一种有希望的新策略，可以预防，停止甚至逆转这种情况。锻炼已被证明是一种有效的认知增强剂，可降低老年个体患AD的风险，但其潜在机制远未得到充分了解。我们探讨了长期的跑步机运动是否会减弱淀粉样蛋白前体蛋白（APP）/早老素-1（PS1）突变诱导的异常网络活动，从而通过改变电压门控钠通道（Nav）的数量和/或分布来提高认知度转基因小鼠。2、3.5、5、6.5、8岁的APP / PS1小鼠 在9个月的跑步机上锻炼了不同的持续时间或不同的AD阶段。记忆，脑电图（EEG）记录以及Nav功能成员的表达水平和分布的变化（Nav1.1α，Nav1.2，Nav1.6，和导航β 2）进行评价。结果显示，跑步机进行为期12周和24周的锻炼1）显着改善了新对象识别（NOR）记忆和莫里斯水迷宫（MWM）空间记忆；2）部分降低异常峰值活动；和3）纠正的干扰Nav1.1的细胞分布α，异常导航β2卵裂增加，和Nav1.6上调。此外，在24周运动组中的APP / PS1小鼠在NOR任务中表现出更好的表现，并且Nav1.6表达大幅下降，接近野生型水平。这项研究表明，运动可以通过改变APP / PS1小鼠海马Nav的数量和分布来改善认知和神经活动。从临床前阶段开始的大约24周的长期跑步机运动是预防AD并阻止其进展的一种有前途的治疗策略。