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

基本信息

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
项目类别：
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&apos s Disease Alzheimer&apos 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

项目摘要

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.

项目概要/摘要由神经退行性疾病（如阿尔茨海默氏病 (AD)）引起的神经损伤是一种主要的、人类研究和动物模型表明，运动对日益增加的健康负担具有神经保护作用。 AD 是一种与β淀粉样蛋白 (Aβ) 负担增加、神经炎症和认知能力下降相关的疾病。运动可减轻 AD 小鼠模型中的 Aβ 负担和神经炎症，并改善认知功能。了解运动这些神经保护作用的潜在分子机制可以导致我们之前发布的数据确定了针对这种疾病的创新治疗方法的开发。新型运动激素 FNDC5（含有 5 的纤连蛋白结构域 III）及其分泌形式，鸢尾素，作为素介导运动的部分神经保护作用的候选者我们已经证明鸢尾素是一种运动- 在小鼠和人类中诱导激素，介导运动对大脑的（部分）有益作用。然而，在使用鸢尾素之前，需要进一步研究鸢尾素如何发挥神经保护作用。根据这些数据，我们发现鸢尾素具有治疗 AD 认知能力下降的作用。 AD 模型体内和体外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) 人类神经细胞培养模型和体内模型来提出假设 AD 的体内转基因小鼠模型，并通过使用机械分子技术、形态学研究和我们将通过解决（目标 1）鸢尾素在体外是否具有神经保护作用来实现这一目标。通过使用 AD 的 3D 人类神经细胞培养模型以及（目标 2）使用鸢尾素在体内是否具有神经保护作用 AD 转基因小鼠模型，以及（目标 3）成功完成的细胞机制。这些实验将有助于更好地理解运动的分子机制此外，它还为鸢尾素如何发挥作用建立了一个框架。可用作治疗 AD 的药物。