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.

项目摘要/摘要 阿尔茨海默病(AD)等神经退行性疾病引起的神经损伤是一种主要的 不断增加的健康负担。运动在人体研究和动物模型中已被证明具有神经保护作用 AD是一种与淀粉样β蛋白(Aβ)增加相关的疾病-负担、神经炎症和认知能力下降。 运动可减轻AD模型小鼠的Aβ负荷和神经炎症，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 开发针对这种疾病的创新治疗方法。我们之前发布的数据表明， 新型运动激素FNDC5(纤维连接蛋白结构域III含5)及其分泌形式--淫羊藿素 候选调节运动的神经保护作用的一部分。我们已经证明了虹膜是一种运动-- 在老鼠和人类中诱导的荷尔蒙，它(部分)调节运动对大脑的有益影响。 然而，在使用淫羊藿素之前，还需要对其神经保护作用进行进一步的机制研究。 治疗阿尔茨海默病认知功能减退。根据这些数据，我们推测淫羊藿素具有 体内和体外AD模型的神经保护作用。这项提案的目标是严格测试这一点 通过整合AD和AIN的体外三维(3D)人类神经细胞培养模型的假说 用转基因小鼠建立AD动物模型，并通过分子机制技术、形态学研究和 行为测试。我们将通过解决(目标1)淫羊藿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和(目标2)淫羊藿素在体内是否具有神经保护作用 阿尔茨海默病转基因小鼠模型，以及(目标3)阿尔茨海默病发生的细胞机制。成功完成 这些实验将提供一个更好的理解运动的分子机制 在神经退行性疾病中提供神经保护。此外，它还建立了一个关于虹膜如何 可作为治疗阿尔茨海默病的药物。