Exploring irisin as a novel target for Alzheimers Disease

探索鸢尾素作为阿尔茨海默病的新靶点

• 批准号: 10670486
• 负责人: SE HOON CHOI
• 金额: $ 78.52万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-15 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10670486
• 关键词: 3-Dimensional; AD transgenic mice; Address; Alzheimer' s Disease; Alzheimer' s disease model; Amyloid; Amyloid beta-Protein; Amyloid beta-Protein Precursor; Animal Model; Astrocytes; Binding; Brain; Cell Culture Techniques; Cells; Clinical Research; Complex; Data; Dementia; Development; Disease; Enzymes; Exercise; Fibronectins; Health; Hormones; Human; Impaired cognition; Impairment; In Vitro; Insulinase; Integrin alphaV; Integrins; Knockout Mice; Lead; Learning; Mediating; Mediator of activation protein; Memory; Memory Loss; Microscopy; Molecular; Morphology; Mus; Neprilysin; Nerve Degeneration; Neurodegenerative Disorders; Neurofibrillary Tangles; Neuroglia; Neurologic; Neurons; Pathologic; Pathology; Pathway interactions; Peripheral; Process; Proteins; Publishing; Recombinants; Role; Senile Plaques; Side; Study models; System; Techniques; Testing; Therapeutic; Therapeutic Uses; Transgenic Mice; Work; age related; amyloid pathology; amyloid precursor protein processing; base; behavior test; beta secretase; cognitive function; experimental study; gamma secretase; hyperphosphorylated tau; improved; in vivo; in vivo Model; induced pluripotent stem cell; innovation; mouse model; neuroinflammation; neuron loss; neuroprotection; new therapeutic target; novel; public health relevance; receptor; single-cell RNA sequencing; tau Proteins; therapeutically effective; three dimensional cell culture; uptake; β-amyloid burden

PROJECT SUMMARY/ABSTRACT Neurological impairment caused by neurodegenerative diseases, such as Alzheimer’s disease (AD), is a major, growing health burden. Exercise has been shown in human studies and animal models to be neuroprotective in AD, a disease associated with an increased Amyloid beta (Aβ)-burden, neuroinflammation, and cognitive decline. Exercise reduces the Aβ-burden and neuroinflammation, and improves cognitive function in AD mouse models. Understanding the underlying molecular mechanism of these neuroprotective effects of exercise can lead to the development of innovative therapeutic approaches for this disorder. Our previously published data identified the novel exercise hormone FNDC5 (fibronectin-domain III containing 5) and its secreted form, irisin, as a prime candidate to mediate part of the neuroprotective effects of exercise. We have shown that irisin is an exercise- induced hormone in mice and humans that mediates (part of) the beneficial effects of exercise on the brain. However, further mechanistic studies on how irisin is neuroprotective are required before irisin could be used therapeutically to treat cognitive decline in AD. Based on these data, we hypothesize that irisin has neuroprotective effects in AD models in vivo and in vitro. The objective for this proposal is to rigorously test this hypothesis by integrating an in vitro three-dimensional (3D) human neural cell culture model of AD and an in vivo transgenic mouse model of AD and by using mechanistic molecular techniques, morphological studies, and behavioral testing. We will achieve this objective by addressing (Aim 1) whether irisin is neuroprotective in vitro by using a 3D human neural cell culture model of AD and (Aim 2) whether irisin is neuroprotective in vivo using a transgenic mouse model of AD, and (Aim 3) by which cellular mechanism that occurs. Successful completion of these experiments will provide a better understanding of the molecular mechanisms whereby exercise provides neuroprotection in neurodegenerative diseases. In addition, it establishes a framework for how irisin could be used as a therapeutic to treat AD.

项目总结/摘要 由神经退行性疾病如阿尔茨海默病（AD）引起的神经损伤是一种主要的， 日益沉重的健康负担。在人类研究和动物模型中，运动已被证明是神经保护性的， AD是一种与淀粉样蛋白β（Aβ）负荷增加、神经炎症和认知能力下降相关的疾病。 运动可降低AD小鼠模型中的Aβ负荷和神经炎症，并改善认知功能。 了解这些运动神经保护作用的潜在分子机制可以导致 为这种疾病开发创新的治疗方法。我们先前公布的数据确定了 新的运动激素FNDC 5（含有5的纤连蛋白-结构域III）及其分泌形式，作为引发剂的鸢尾素， 候选人调解运动的神经保护作用的一部分。我们已经证明了Irisin是一种练习- 在小鼠和人类中诱导激素，介导（部分）运动对大脑的有益影响。 然而，在使用鸢尾素之前，还需要对鸢尾素如何具有神经保护作用进行进一步的机制研究 治疗AD中的认知下降。基于这些数据，我们假设Irisin具有 在体内和体外AD模型中的神经保护作用。该提案的目的是严格测试这一点 通过整合AD的体外三维（3D）人神经细胞培养模型和一种在体外的神经细胞培养模型， AD的体内转基因小鼠模型，并使用机械分子技术，形态学研究， 行为测试我们将通过解决（目标1）鸢尾素是否在体外具有神经保护作用来实现这一目标 通过使用AD的3D人神经细胞培养模型和（目的2）使用A1000是否在体内具有神经保护作用， AD的转基因小鼠模型，以及（目的3）通过其发生的细胞机制。成功完成 这些实验将提供一个更好的理解的分子机制， 在神经退行性疾病中提供神经保护。此外，它还建立了一个框架， 可以作为治疗AD的药物。