Protective effects of exercise against Alzheimer's disease in a transgenic rat model

运动对转基因大鼠模型中阿尔茨海默病的保护作用

• 批准号: 10246249
• 负责人: Stephanie E Hall
• 金额: $ 7.03万
• 依托单位: KANSAS STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-01 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10246249
• 关键词: Age-Months; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease risk; American; Amyloid beta-Protein; Amyloid beta-Protein Precursor; Animal Diseases; Animal Model; Animal Testing; Animals; Apoptosis; Attenuated; Behavioral; Biochemical; Biological Markers; Birth; Blood; Blood Circulation; Brain; Brain-Derived Neurotrophic Factor; Cell Survival; Cerebrospinal Fluid; Cerebrum; Cleaved cell; Cognition; Development; Disease; Disease model; Elderly; Exercise; Gene Proteins; Genomics; Genotype; Harvest; Hormones; Human; Impaired cognition; Impairment; Intervention; Light; Link; Long-Term Potentiation; Mainstreaming; Measures; Memory; Methods; Modeling; Molecular; Muscle; Nature; Neurofibrillary Tangles; Neurons; Pathologic; Pathology; Pathway interactions; Patients; Pharmacology; Physiological; Play; Proteomics; Race; Rat Strains; Rattus; Research; Research Personnel; Risk; Role; Signal Transduction; Skeletal Muscle; Tauopathies; Testing; Time; TimeLine; Tissues; Transgenic Animals; Transgenic Organisms; Universities; abeta accumulation; age related; aging brain; brain tissue; brain volume; exercise training; fight against; human disease; improved; innovation; interest; invention; migration; muscle strength; neuron loss; neuroprotection; novel; preempt; protective effect; sedentary; synaptogenesis; tau Proteins; tool; transgenic model of alzheimer disease; treadmill training

ABSTRACT Nearly 6 million Americans suffer from Alzheimer's disease (AD) and that number is expected to rise to 14 million by 2050 (1). Currently there is no cure or even a treatment to slow its progression, however, exercise has proven to reduce your risk (5-9,60,61). Several studies have linked exercise to improved cognition and increased brain volume in AD (10,62-64). This project will shed light on the mechanisms behind this protection, to not only promote exercise as a preventative tool but to also unveil potential pathways for pharmacological intervention in those patients unable to exercise. Two mainstream hypotheses exist for the exercise-induced protection against AD. One is that exercise increases brain-derived neurotrophic factor (BDNF) which plays a role in promoting brain plasticity and long-term potentiation (65). The second is that exercise protects against AD by reducing the development of plaque (amyloid-β) and tangles (tau protein). Due to the nature and complexity of the disease, researching a cure or treatment has been difficult. However, a rat strain has recently been developed (TgF344-AD) that displays a complete repertoire of AD pathological features, including, age- dependent accumulation of cerebral amyloid-β that preempts tauopathy, cognitive disturbance, apoptosis, and neuronal loss (66). This strain will be key to the greater understanding of the human disease. With this project, I plan to 1) establish a timeline of the exercise-induced protect against AD in this novel transgenic model of AD and 2) shed light on the mechanisms of protection. To accomplish this, TgF344-AD animals will be bred at Boise State University. Following genotyping, they will be placed in either an AD or wild type group. Additionally, they will be divided into either sedentary or exercise group. While the sedentary group will be restricted to cage activity, the exercise group will be treadmill trained 5 days per week for 6 months. Every 3 months from birth to 18 months, all animals will be assessed for memory, coordination and muscular strength. At 18 months of age, brain, skeletal muscle, cerebrospinal fluid and blood will be harvested and biochemical analysis will be conducted. Among the proposed analyses, we will measure FNDC5/Irisin in all the tissues. This is an important project that will provide valuable information to researchers working with this novel model of AD. In addition, it will determine the role of FNDC5/Irisin pathway in the exercise-induced neuroprotection. This project will serve as a significant step in the fight against Alzheimer's disease.

摘要 近600万美国人患有阿尔茨海默病（AD），预计这一数字将上升到14 到2050年（1）。目前还没有治愈甚至治疗方法来减缓其进展，然而，运动 已证明可降低风险（5- 9，60，61）。一些研究已经将锻炼与提高认知能力联系起来， 增加AD患者的脑容量（10，62 -64）。该项目将揭示这种保护背后的机制， 不仅促进运动作为一种预防工具，而且还揭示了药理学的潜在途径， 对那些无法锻炼的患者进行干预。对于运动诱发的 预防AD。一种是运动增加了脑源性神经营养因子（BDNF）， 促进大脑可塑性和长时程增强的作用（65）。第二，锻炼可以防止 通过减少斑块（淀粉样蛋白-β）和缠结（tau蛋白）的发展来治疗AD。由于性质和 由于疾病的复杂性，研究治愈或治疗方法一直很困难。然而，最近一种老鼠 已经开发出了TgF 344-AD，其显示出AD病理学特征的完整库，包括，年龄- 脑淀粉样蛋白-β的依赖性积累，抢先于tau蛋白病、认知障碍、细胞凋亡和 神经元丢失（66）。这种菌株将是进一步了解人类疾病的关键。有了这个项目， 本研究拟1）建立运动诱导的抗AD转基因动物模型的时间轴 （2）阐明保护机制。为了实现这一点，TgF 344-AD动物将在 博伊西州立大学。在基因分型后，将它们置于AD或野生型组中。 此外，他们将被分为久坐或运动组。而久坐不动的一组 仅限于笼内活动，运动组每周进行5天跑步机训练，持续6个月。每3 从出生到18个月，所有动物都将接受记忆力、协调性和肌肉力量评估。 在18个月大时，将收获脑、骨骼肌、脑脊液和血液并进行生化检查。 将进行分析。在提出的分析中，我们将测量所有组织中的FNDC 5/Irisin。 这是一个重要的项目，将为研究这种新型模型的研究人员提供有价值的信息 的AD。此外，还将探讨FNDC 5/Irisin通路在运动性神经保护中的作用。 该项目将成为对抗阿尔茨海默病的重要一步。