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: 10596060
• 负责人: Fabrisia Ambrosio
• 金额: $ 76.41万
• 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/10596060
• 关键词: Acute; Aerobic Exercise; Affect; Aging; Alleles; Alzheimer like pathology; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease patient; Alzheimer' s disease risk; Amyloid; Animal Disease Models; Animal Model; Behavioral; Bioenergetics; Biology; Blood; Brain; Cells; Cellular biology; Characteristics; Choroid Plexus Epithelium; Circulation; Cognition; Cognitive; Communication; Complex; Data; Diet; Disease associated microglia; Disease model; Environmental Risk Factor; Epithelial Cells; Exercise; Gene Expression; Genes; Genetic; Goals; Hippocampus; Human; Impaired cognition; Impairment; In Vitro; Infiltration; Inflammatory; Injections; Interdisciplinary Study; Kidney; Laboratories; Late Onset Alzheimer Disease; Life Style; Link; Longevity; Macrophage; Maintenance; Mediating; Mediator; Memory; Messenger RNA; MicroRNAs; Molecular; Morphology; Mus; Muscle; Muscle Cells; Muscle Contraction; Muscle satellite cell; NIH Program Announcements; Nerve Degeneration; Neurodegenerative Disorders; Outcome; Pathogenesis; Peripheral; Phenotype; Physical Exercise; Physical activity; Plasma; 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; mouse model; muscle aging; muscle regeneration; neural; neuromuscular stimulation; neuroprotection; novel; overexpression; programs; resilience; response; transcriptome; transmission process; 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.

衰老是阿尔茨海默氏病（AD）的主要危险因素。许多研究证实了体育锻炼 对AD和其他神经退行性疾病患者具有积极影响。大多数研究 在神经退行性动物模型中，体育锻炼的作用报告了神经保护作用，改善了 记忆和认知表现。非神经元之间相互作用的分子机制 然而，与身体/有氧运动有关的系统和大脑涉及的系统仍然了解得很糟糕。这 抗炎蛋白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蛋白的升高或注射固体α-Klotho片段，认知增强和 年轻，衰老和鼠类疾病模型的神经弹性。最近的报告表明α-Klotho水平 AD动物模型的大脑减少。最近已经显示，物理有氧运动增加了 循环水平的α-Klotho水平，我们发现通过神经肌肉电气直接肌肉收缩 刺激显着增强了海马中的α-klotho表达。这些发现提出了小说 假设骨骼肌可能是循环α-Klotho的调节剂。我们肯定肌肉引起的模拟 α-klotho的作用可能在运动对认知结果的有益作用中发挥作用。重要的是，已经 确定从外围到中枢神经系统的信号通过高度特异性的机制传输 丛（CP）上皮，体育锻炼增加了细胞外蔬菜的释放和数量 我们的初步数据表明，在从中分离出来的外泌体中，可以在高水平上检测到α-klotho 血浆，肌肉收缩活性增加了含α-klotho的外泌体的释放和量 循环。我们还表明，外泌体货物可以在体外传输信号，从而影响表达 细胞内蛋白水平。我们假设体育锻炼对中枢神经系统的影响是信号的结果 在周围肌肉中产生，并通过CP上皮传播到大脑。信号是关联的 并取决于并取决于抗衰老蛋白的循环水平增加，α-klotho，由肌肉释放 外泌体。这项跨学科研究将使广告研究人员与广告动物的专业知识相结合 建立研究人员 在α-klotho的生物学中，康复和衰老（F. ambrosio）和细胞生物学（C. st Croix）。该提议的目标 是为了进一步了解骨骼肌中α-klotho表达之间的相互作用，体育锻炼 和大脑，并阐明与年龄相关的骨骼肌变化与AD的进展的关系。目标1： 确定体育锻炼对海马和皮质中表型和基因表达的影响是否 由α-Klotho介导。目标2：揭示肌肉训练对等离子体和CSF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相结合。目标3：到 阐明了脉络丛和α-klotho在从周围肌肉传达信号中的作用。