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.

大量研究证实，衰老是阿尔茨海默病（AD）的主要危险因素。 大多数研究都对 AD 和其他神经退行性疾病患者有积极作用。 据报道，体育锻炼对神经退行性变动物模型的神经保护作用、改善作用 非神经元之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。 抗衰老蛋白 α-Klotho 具有众所周知的神经保护活性，最近的研究表明系统性 转基因小鼠体内α-Klotho蛋白升高或注射可溶性α-Klotho片段，增强认知能力 最近的报告表明，年轻、衰老和小鼠疾病模型中的 α-Klotho 水平存在差异。 最近的研究表明，有氧运动可以增加 AD 动物模型大脑的衰退。 α-Klotho 的循环水平，我们发现通过神经肌肉电直接肌肉收缩 刺激增强了海马中的 α-Klotho 表达，这些发现提出了显着的新颖性。 假设骨骼肌可能是循环 α-Klotho 的调节器，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着重要作用。 确定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输的 神经丛 (CP) 上皮细胞，体育锻炼会增加细胞外囊泡的释放和数量 我们的初步数据表明，在分离的外泌体中可检测到高水平的 α-Klotho。 血浆中，肌肉收缩活动增加了含有 α-Klotho 的外泌体的释放和数量 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。 我们发现体育锻炼对中枢神经系统的影响是信号的结果。 这些信号在周围肌肉中产生并通过 CP 上皮传输到大脑。 并依赖于体内肌肉释放的抗衰老蛋白 α-Klotho 循环水平的增加 这项跨学科研究将整合 AD 研究人员在 AD 动物方面经验丰富的专业知识。 模型、AD 样病理学分析和混合方法（R. Koldamova 和 I. Lefterov），知名研究人员 α-Klotho 生物学、康复和衰老（F. Ambrosio）和细胞生物学（C. St Croix） 该提案的目标。 是为了进一步了解骨骼肌中 α-Klotho 表达与身体活动之间的相互作用 和大脑，并阐明骨骼肌与年龄相关的变化与 AD 进展的关系。 确定体育锻炼是否对海马体和皮质的表型和基因表达产生影响 由 α-Klotho 介导 目标 2：揭示肌肉训练对血浆和脑脊液中外泌体货物的影响， 并将其蛋白质组和 miRNA 谱与表型和大脑转录组整合起来。 目标 3： 阐明脉络丛和 α-Klotho 在将信号从周围肌肉传递到中枢神经系统中的作用。