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

体育锻炼和血脑通讯：外泌体、Klotho 和脉络丛

• 批准号: 10083686
• 负责人: Fabrisia Ambrosio
• 金额: $ 77.25万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-01-15 至 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10083686
• 关键词: Acute; Address; Aerobic Exercise; Affect; Aging; Alleles; Alzheimer like pathology; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease risk; Amyloid; Animal Disease Models; Animal Model; Behavioral; Bioenergetics; Biology; Blood; Blood Circulation; Brain; Cells; Cellular biology; Characteristics; Choroid Plexus Epithelium; Cognition; Cognitive; Communication; Complex; Data; Diet; Disease; Disease model; Environmental Risk Factor; Epithelial Cells; Exercise; Gene Expression; Genes; Genetic; Goals; Hippocampus (Brain); Human; Impaired cognition; Impairment; In Vitro; Infiltration; Inflammatory; Injections; Interdisciplinary Study; Kidney; Laboratories; Late Onset Alzheimer Disease; Life Style; Link; Longevity; Maintenance; Mediating; Mediator of activation protein; Memory; Messenger RNA; MicroRNAs; Microglia; Molecular; Morphology; Mus; Muscle; Muscle Cells; Muscle Contraction; Muscle satellite cell; NIH Program Announcements; Nerve Degeneration; Neurodegenerative Disorders; Outcome; Pathogenesis; Patients; Peripheral; Phenotype; Physical Exercise; Physical activity; Plasma; Play; Procedures; Proteins; Proteomics; Rattus; Regulation; Rehabilitation therapy; Reporting; Research; Research Design; Research Personnel; Risk; Risk Factors; Role; Running; Senile dementia; Signal Transduction; Skeletal Muscle; Skeletal muscle injury; Structure of choroid plexus; System; Testing; Time; Training; Transgenic Mice; Up-Regulation; age related; aging brain; anti aging; cognitive function; cognitive performance; exosome; experience; extracellular vesicles; improved; in vitro Model; klotho protein; mRNA Expression; macrophage; mouse model; muscle aging; muscle regeneration; neuromuscular stimulation; neuroprotection; novel; overexpression; programs; relating to nervous system; resilience; response; transcriptome; treadmill

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.

衰老是阿尔茨海默病(AD)的主要危险因素。许多研究已经证实，体育锻炼 对AD和其他神经退行性疾病患者有积极作用。大多数研究都在考察 运动对神经退行性变动物模型的影响已有报道，神经保护作用有所改善 记忆力和认知能力。非神经细胞间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。这个 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，全身性 转基因小鼠中α-klotho蛋白的升高或注射可溶性α-klotho片段，增强认知和 年轻、衰老和小鼠疾病模型中的神经韧性。最近的报告表明，α-Klotho水平 阿尔茨海默病动物模型脑功能衰退。最近的研究表明，体育有氧运动增加了 循环中的α-Klotho水平，我们发现通过神经肌肉电直接收缩肌肉 刺激显著增强α-klotho在海马区的表达。这些发现提升了这部小说 骨骼肌可能是循环α-Klotho的调节者的假说。我们假设肌肉诱导的刺激 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，它一直是 确立了从外周到中枢神经系统的信号是通过高度特异的脉络膜机制传递的 神经丛(CP)上皮，运动增加细胞外小泡的释放和进入细胞内的数量 发行量。我们的初步数据表明，在分离自日本血吸虫的外体中可以检测到高水平的α-Klotho 血浆，而肌肉收缩活动增加了含有α-Klotho的外切体的释放和数量 发行量。我们还表明，外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。我们假设，体育锻炼对中枢神经系统的影响是信号的结果 产生于外周肌肉，并通过CP上皮传递到大脑。这些信号是关联的 随着并依赖于循环中抗衰老蛋白水平的增加，α-Klotho由体内肌肉释放 外显体。这项跨学科的研究将整合AD研究人员在AD动物方面的经验 模型，AD样病理分析和OMIX方法(R.KolDamova和I.Lefterov)，公认的研究人员 α-Klotho生物学、康复和衰老(F.Ambrosio)和细胞生物学(C.St Croix)。这项提案的目标是 是为了加深我们对α-Klotho在骨骼肌中的表达、运动之间的相互作用的理解 并阐明骨骼肌的增龄性变化与AD进展的关系。目标1： 确定体育锻炼是否对海马区和大脑皮层的表型和基因表达产生影响 都是由α-Klotho调解的。目的2：揭示肌肉训练对血浆和脑脊液中胞外液含量的影响。 并将它们的蛋白质组和miRNA图谱与表型和脑转录组相结合。目标3：实现 阐明脉络丛和α-klotho在外周肌肉向中枢神经系统传递信号中的作用。