Exploring irisin as a novel target for Alzheimer's Disease

探索鸢尾素作为阿尔茨海默病的新靶点

• 批准号: 9919511
• 负责人: SE HOON CHOI
• 金额: $ 21万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-05-01 至 2021-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9919511
• 关键词: 3-Dimensional; AD transgenic mice; Address; Adult; Alzheimer' s Disease; Alzheimer' s disease model; Amyloid beta-Protein; Amyloid beta-Protein Precursor; Animal Disease Models; Animal Model; Antibodies; Biological; Biological Assay; Biological Models; Brain; CASP3 gene; Cell Count; Cell Culture Techniques; Cell Survival; Clinical Research; Clinical Trials; Data; Dementia; Disease; Enzyme-Linked Immunosorbent Assay; Exercise; Failure; Fibronectins; Genes; Health; Hippocampus (Brain); Hormones; Human; Immunofluorescence Immunologic; Impaired cognition; Impairment; In Vitro; Injections; Learning; Life; Mediating; Mediator of activation protein; Memory; Memory Loss; Molecular; Morphology; Mus; Nerve Degeneration; Neurodegenerative Disorders; Neurofibrillary Tangles; Neurologic; Neurons; Pathologic; Pathology; Peripheral; Process; Proteins; Publishing; Recombinants; Senile Plaques; Side; Staining and Labeling; Study models; Tail; Techniques; Testing; Therapeutic; Therapeutic Uses; Transgenic Mice; Treatment Efficacy; United States National Institutes of Health; Veins; Western Blotting; age related; amyloid pathology; base; behavior test; beta secretase; cognitive function; drug discovery; experimental study; gamma secretase; hyperphosphorylated tau; improved; in vivo; in vivo Model; innovation; morris water maze; mouse model; nervous system disorder; neurogenesis; neuroinflammation; neuron loss; neuroprotection; neurotrophic factor; new therapeutic target; novel; presenilin-1; public health relevance; response; tau Proteins; three dimensional cell culture; β-amyloid burden

PROJECT SUMMARY/ABSTRACT This application titled “Exploring irisin as a novel target for Alzheimer’s Disease” is submitted in response to NIH PAR-16-042: Drug Discovery for Nervous System Disorders (R21). Neurological impairment caused by neurodegenerative diseases, such as Alzheimer’s disease (AD), is a major and growing health burden. Exercise has been shown in human studies and animal models to be neuroprotective in AD. AD is associated with an increased Amyloid beta (Aβ)-burden, impaired hippocampal neurogenesis, and cognitive decline. Exercise reduces the Aβ-burden, restores neurogenesis, and improves cognitive function in AD mouse models. Understanding the underlying molecular mechanism of these neuroprotective effects of exercise has the potential for developing 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. Notably, the elevation of circulating irisin levels was sufficient to induce the expression of the important neurotrophin Bdnf and other neuroprotective genes in the hippocampus. Furthermore, the addition of recombinant irisin to a three-dimensional (3D) human neural cell culture model of AD reduced neuronal cell death. 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 3D human neural cell culture model of AD and an in vivo transgenic mouse model of AD and using mechanistic molecular techniques, morphological studies, and behavioral testing. We will achieve this objective by addressing (Aim 1) whether irisin is neuroprotective in vitro 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. Successful completion of these experiments will provide a better understanding of the molecular mechanisms whereby exercise provide 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 该申请标题为“探索虹膜素作为阿尔茨海默氏病的新目标”，以响应NIH提交 PAR-16-042：神经系统疾病的药物发现（R21）。由 神经退行性疾病，例如阿尔茨海默氏病（AD），是一种主要且日益增长的健康伯恩。锻炼 在人类研究和动物模型中已显示出AD的神经保护作用。广告与 淀粉样蛋白β（Aβ）的增加，海马神经发生受损和认知能力下降。锻炼 减少了Aβ-负担，恢复神经发生并改善AD小鼠模型中的认知功能。 了解这些神经保护作用的潜在分子机制具有 为这种疾病开发创新的治疗方法的潜力。我们先前发布的数据 将新颖的运动马龙FNDC5（纤连蛋白域III）识别 介导一部分运动神经保护作用的主要候选者。我们已经证明虹膜蛋白是 运动引起的锻炼的同性恋者和人类介导的（一部分）运动对锻炼的有益作用 脑。值得注意的是，循环虹膜蛋白水平的升高足以诱导重要的表达 海马中的神经营养蛋白BDNF和其他神经保护基因。此外，增加 重组虹膜蛋白至三维（3D）AD还原神经元细胞的三维（3D）人神经元细胞培养模型 死亡。但是，在虹膜蛋白之前，需要关于虹膜蛋白是如何具有神经保护性的进一步机械研究 用热治疗AD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。该提议的目的是严格测试 通过整合AD的体外3D人神经元细胞培养模型和体内转基因小鼠的假设 AD的模型和使用机械分子技术，形态学研究和行为测试。我们 将通过解决（AIM 1）使用3D人的体外神经保护作用来实现这一目标 AD的神经细胞培养模型和（AIM 2）Irisin是否使用转基因小鼠在体内神经保护 AD模型。这些实验的成功完成将更好地理解分子 运动在神经退行性疾病中提供神经保护作用的机制。另外，它 建立一个框架，即如何将虹膜蛋白用作治疗AD的治疗方法。