阿尔茨海默氏症小鼠模型的神经肌肉功能障碍先于认知功能受损

IF 5.1 Q2 CELL BIOLOGY Function (Oxford, England) Pub Date : 2023-12-04 eCollection Date: 2024-01-01 DOI:10.1093/function/zqad066
Matthew H Brisendine, Anna S Nichenko, Aloka B Bandara, Orion S Willoughby, Niloufar Amiri, Zach Weingrad, Kalyn S Specht, Jacob M Bond, Adele Addington, Ronald G Jones, Kevin A Murach, Steven Poelzing, Siobhan M Craige, Robert W Grange, Joshua C Drake
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引用次数: 0

摘要

阿尔茨海默病(AD)的发病过程是一个连续的过程,在确诊前数年就会出现。肌肉功能和线粒体呼吸功能的减退早在几年前就出现在阿兹海默症患者身上;然而,人们还不知道是什么原因导致这些外周表型出现在脑部疾病中。运动能促进肌肉、线粒体和认知健康,被认为是一种潜在的AD治疗方法,但还没有研究调查过骨骼肌在类似AD的情况下是如何适应运动训练的。我们利用 5xFAD 小鼠(一种在 6 个月左右出现类似 AD 病理和认知障碍的 AD 模型),在明显的认知障碍出现之前检查了体内神经肌肉功能和运动适应性(线粒体呼吸和 RNA 测序)。我们发现 5xFAD 小鼠早在 4 月龄时就出现了神经肌肉功能障碍,其特征是神经刺激肌肉产生的扭矩和坐骨神经的复合神经动作电位受损。此外,在没有明显认知障碍的情况下,5xFAD 小鼠的骨骼肌对运动训练的适应性反应(线粒体呼吸和基因表达)发生了改变,且这种改变与性别有关。外周系统的变化,特别是神经与骨骼肌之间的交流,可能是注意力缺失症的先兆,并对注意力缺失症患者的生活方式干预(如运动)产生影响。
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Neuromuscular Dysfunction Precedes Cognitive Impairment in a Mouse Model of Alzheimer's Disease.

Alzheimer's disease (AD) develops along a continuum that spans years prior to diagnosis. Decreased muscle function and mitochondrial respiration occur years earlier in those that develop AD; however, it is unknown what causes these peripheral phenotypes in a disease of the brain. Exercise promotes muscle, mitochondria, and cognitive health and is proposed to be a potential therapeutic for AD, but no study has investigated how skeletal muscle adapts to exercise training in an AD-like context. Utilizing 5xFAD mice, an AD model that develops ad-like pathology and cognitive impairments around 6 mo of age, we examined in vivo neuromuscular function and exercise adapations (mitochondrial respiration and RNA sequencing) before the manifestation of overt cognitive impairment. We found 5xFAD mice develop neuromuscular dysfunction beginning as early as 4 mo of age, characterized by impaired nerve-stimulated muscle torque production and compound nerve action potential of the sciatic nerve. Furthermore, skeletal muscle in 5xFAD mice had altered, sex-dependent, adaptive responses (mitochondrial respiration and gene expression) to exercise training in the absence of overt cognitive impairment. Changes in peripheral systems, specifically neural communication to skeletal muscle, may be harbingers for AD and have implications for lifestyle interventions, like exercise, in AD.

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