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 这份名为《探索淫羊藿素作为治疗阿尔茨海默氏症的新靶点》的申请是对美国国立卫生研究院的回应 PAR-16-042：神经系统疾病的药物发现(R21)。由以下原因引起的神经功能损害 神经退行性疾病，如阿尔茨海默病(AD)，是一个主要的且不断增长的健康负担。锻炼 人类研究和动物模型表明，阿尔茨海默病具有神经保护作用。广告与一个 淀粉样β蛋白(Aβ)负荷增加，海马神经发生受损，认知能力下降。锻炼 减轻Aβ负荷，恢复神经再生，改善AD模型小鼠的认知功能。 了解这些运动神经保护作用的潜在分子机制 开发治疗这种疾病的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FNDC5(纤维连接蛋白结构域III包含5)及其分泌形式虹膜蛋白为 是调节运动的部分神经保护作用的最佳候选者。我们已经证明了淫羊藿素是一种 运动诱导荷尔蒙在小鼠和人类中介导运动对健康的有益影响(部分) 大脑。值得注意的是，循环中虹膜蛋白水平的升高足以诱导重要的 海马区的神经营养因子、脑源性神经营养因子和其他神经保护基因。此外，增加了 重组淫羊藿素对AD变性神经细胞三维培养模型的研究 死亡。然而，在虹膜素能发挥神经保护作用之前，还需要进一步的机制研究。 用于治疗阿尔茨海默病的认知功能衰退。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 整合AD体外3D人类神经细胞培养模型和体内转基因小鼠的假说 应用机械性分子技术、形态学研究和行为学测试等方法建立AD模型。我们 将通过使用3D人体来解决(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 阿尔茨海默病的神经细胞培养模型及转基因小鼠体内淫羊藿素是否具有神经保护作用 AD的模型。这些实验的成功完成将提供对分子的更好的理解 运动在神经退行性疾病中提供神经保护的机制。此外，它还 建立了一个框架，如何使用虹膜可以作为治疗阿尔茨海默病的治疗。