Physical exercise and Blood-brain communication: exosomes, Klotho and choroid plexus

衰老是阿尔茨海默病（AD）的主要危险因素。许多研究证实，体育锻炼 对AD和其他神经退行性疾病患者有积极作用。大多数研究都是 体育锻炼在神经退行性疾病动物模型中的效果已经报道了神经保护，改善 记忆和认知能力。非神经元与神经元相互作用的分子机制 然而，参与身体/有氧运动和大脑的系统仍然知之甚少。的 抗衰老蛋白α-Klotho具有众所周知的神经保护活性，最近的研究表明， 在转基因小鼠中升高α-Klotho蛋白或注射可溶性α-Klotho片段，增强认知能力， 年轻人、老年人和鼠疾病模型中的神经弹性。最近的报告表明，α-Klotho水平 AD动物模型的脑功能下降。最近的研究表明，有氧运动可以增加 循环水平的α-Klotho，我们已经发现，直接肌肉收缩，通过神经肌肉电 刺激显著增强海马中α-Klotho的表达。这些发现使小说 假设骨骼肌可能是循环α-Klotho的调节剂。我们认为肌肉刺激 α-Klotho可能在运动对认知结果的有益影响中发挥作用。重要的是， 建立了从外周到中枢神经系统的信号是通过脉络膜高度特异性的机制传递的 神经丛（CP）上皮，体育锻炼增加细胞外囊泡的释放和数量， 流通我们的初步数据表明，α-Klotho在从大肠杆菌分离的外泌体中以高水平可检测到。 肌肉收缩活动增加了血浆中含有α-Klotho的外泌体的释放和量。 流通我们还表明，外泌体货物可以在体外向细胞传递信号，从而影响表达。 细胞内蛋白质水平。我们推测，运动对中枢神经系统的影响是信号的结果 在外周肌肉中产生并通过CP上皮传递到大脑。这些信号与 随着并依赖于抗衰老蛋白α-Klotho循环水平的增加，α-Klotho由体内肌肉释放， 外来体这项跨学科的研究将整合AD研究人员的专业知识， 模型、AD样病理分析和omix方法（R.科尔达莫瓦岛Lefterov），既定研究人员 在α-Klotho，康复和衰老的生物学（F。Ambrosio）和细胞生物学（C.圣克罗伊）。这项提案的目的是 是为了进一步了解α-Klotho在骨骼肌中的表达， 和脑组织的变化，并阐明骨骼肌的年龄相关性变化与AD进展的关系。目标1： 为了确定体育锻炼是否对海马和皮层的表型和基因表达的影响， 由α-Klotho介导。目的2：揭示肌肉训练对血浆和脑脊液中外泌体货物的影响， 并将其蛋白质组学和miRNA谱与表型和脑转录组整合。目标3： 阐明脉络丛和α-Klotho在外周肌肉向CNS传递信号中的作用。

Aging is the major risk factor for Alzheimer’s disease (AD). Numerous studies have confirmed that physical exercise has positive effects in patients with AD and other neurodegenerative disorders. The majority of the studies examining the effect of physical exercise in animal models of neurodegeneration have reported neuroprotection, improved memory and cognitive performance. The molecular mechanisms of the interactions between the non-neuronal systems involved in the physical/aerobic exercise and brain, however, remain poorly understood. The antiaging protein, α-Klotho, has well-known neuroprotective activity, and recent studies demonstrated that systemic elevation of α-Klotho protein in transgenic mice or injection of soluble α-Klotho fragment, enhanced cognition and neural resilience in young, aging, and a murine disease model. Recent reports have suggested that α-Klotho levels decline in brain of animal models of AD. It has been recently shown that physical aerobic exercise increases the circulating levels of α-Klotho, and we have found that direct muscle contraction via neuromuscular electrical stimulation significantly enhanced α-Klotho expression in the hippocampus. These findings raised the novel hypothesis that skeletal muscle may be a regulator of circulating α-Klotho. We posit that muscle-induced stimulation of α-Klotho may play a role in the beneficial effect of exercise on cognitive outcomes. Importantly, it has been established that signals from periphery to the CNS are transmitted through mechanisms highly specific to choroid plexus (CP) epithelium, and physical exercise increases the release and amount of extracellular vesicles into the circulation. Our preliminary data demonstrate that α-Klotho is detectable at high levels in exosomes isolated from plasma, and that muscle contractile activity increases the release and amount of α-Klotho-containing exosomes in circulation. We also show that the exosomal cargo can transmit a signal to cells in vitro, thus affecting the expression level of intracellular proteins. We hypothesize that the effects of physical exercise on CNS are results of signals generated in peripheral muscles and transmitted to the brain via the CP epithelium. The signals are associated with and depend on increased circulating levels of anti-aging protein,α-Klotho, released by muscles within exosomes. This interdisciplinary research will integrate the expertise of AD researchers experienced with AD animal models, analysis of AD-like pathology and omix approaches (R. Koldamova & I. Lefterov), established researchers in biology of α-Klotho, rehabilitation, and aging (F. Ambrosio) and cell biology (C. St Croix). The goal of this proposal is to further our understanding of the interactions between α-Klotho expression in skeletal muscles, physical activity and brain, and to elucidate the relationship of age-related changes in skeletal muscle and progression of AD. Aim 1: To determine if the effects of physical exercise on phenotype and gene expression in the hippocampus and cortex are mediated by α-Klotho. Aim 2: To reveal the effect of muscle training on exosomal cargo in plasma and CSF, and to integrate their proteomic and miRNA profiles with the phenotype and brain transcriptomes. Aim 3: To elucidate the role of Choroid Plexus and α-Klotho in communicating signals from peripheral muscles to CNS.