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.

项目总结/摘要 这项名为“探索鸢尾素作为阿尔茨海默病的新靶点”的申请是为了回应NIH而提交的。 PAR-16-042：神经系统疾病的药物发现（R21）。神经功能损害， 神经退行性疾病，如阿尔茨海默病（AD），是一个主要的和不断增长的健康负担。行使 已经在人类研究和动物模型中显示出对AD具有神经保护作用。AD与 β淀粉样蛋白（Aβ）负荷增加、海马神经发生受损和认知能力下降。行使 在AD小鼠模型中降低Aβ负荷，恢复神经发生，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， 为这种疾病开发创新治疗方法的潜力。我们之前公布的数据 鉴定了新的运动激素FNDC 5（含有5的纤连蛋白结构域III）及其分泌形式的鸢尾素， 是调节运动的部分神经保护作用的主要候选者。我们已经证明，Irisin是一种 运动诱导的激素在小鼠和人类中介导（部分）运动对 个脑袋值得注意的是，循环鸢尾素水平的升高足以诱导重要的免疫调节因子的表达。 神经营养因子BDNF和其他神经保护基因在海马。此外，添加 将重组鸢尾素应用于AD减少的神经元细胞的三维（3D）人神经细胞培养模型 死亡然而，在鸢尾素可以用于神经保护之前，还需要对鸢尾素如何具有神经保护作用的进一步机制研究。 用于治疗AD的认知能力下降。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3D人神经细胞培养模型和体内转基因小鼠的假设 AD模型，并使用机械分子技术，形态学研究和行为测试。我们 将通过使用3D人体在体外解决（Aim 1）鸢尾素是否具有神经保护作用来实现该目的 AD的神经细胞培养模型和（目的2）使用转基因小鼠在体内是否具有神经保护作用 AD模型这些实验的成功完成将使我们更好地了解 运动在神经退行性疾病中提供神经保护的机制。此外还 建立了一个框架，如何鸢尾素可用作治疗AD的治疗。