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

基本信息

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
项目类别：
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&apos s Disease Alzheimer&apos 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

项目摘要

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.

项目概要/摘要该申请题为“探索鸢尾素作为阿尔茨海默病的新靶点”，是为了回应 NIH 提交的 PAR-16-042：治疗神经系统疾病（R21）引起的神经功能障碍的药物发现。神经退行性疾病，例如阿尔茨海默氏病 (AD)，是一项日益严重的主要健康负担。人类研究和动物模型已显示其对 AD 具有神经保护作用，与 AD 相关。 β 淀粉样蛋白 (Aβ) 负担增加、海马神经发生受损和认知能力下降。减少 AD 小鼠模型中的 Aβ 负担、恢复神经发生并改善认知功能。了解运动这些神经保护作用的潜在分子机制有助于我们之前发布的数据显示了针对这种疾病的创新治疗方法的潜力。鉴定出新型运动激素 FNDC5（含有 5 的纤连蛋白结构域 III）及其分泌形式鸢尾素鸢尾素是介导运动部分神经保护作用的主要候选者。小鼠和人类中运动诱导的激素，介导运动对身体（部分）的有益影响值得注意的是，循环鸢尾素水平的升高足以诱导重要的表达。此外，还添加了海马中的神经营养素 Bdnf 和其他神经保护基因。重组鸢尾素至 AD 神经细胞三维 (3D) 人类神经细胞培养模型然而，在鸢尾素被应用之前，还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 体外 3D 人类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。将通过使用 3D 人体来解决（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 AD 神经细胞培养模型以及（目标 2）使用转基因小鼠鸢尾素是否具有体内神经保护作用 AD模型的成功完成将有助于更好地理解分子。此外，它还具有在神经退行性疾病中发挥神经保护作用的机制。建立了如何使用鸢尾素作为 AD 治疗药物的框架。