Multi-Modal MRI to Assess Alzheimer's Disease Prevention in an APOE4 Mouse Model

多模态 MRI 评估 APOE4 小鼠模型中阿尔茨海默病的预防

• 批准号: 9519808
• 负责人: Ai-Ling Lin
• 金额: $ 53.83万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-07-01 至 2022-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9519808
• 关键词: Aftercare; Alleles; Alzheimer disease prevention; Alzheimer' s Disease; Alzheimer' s disease risk; Amyloid beta-Protein; Animal Model; Animals; Apolipoproteins; Biochemical; Biological Assay; Blood - brain barrier anatomy; Blood Vessels; Brain; Cerebrovascular Circulation; Clinical Trials; Cognitive; Dementia; Development; Diet; Dietary Intervention; Disease Progression; Early Intervention; Effectiveness; FDA approved; FRAP1 gene; Functional disorder; Future; Genes; Goals; Human; Impaired cognition; Impairment; Inflammation; Intervention; Magnetic Resonance Imaging; Measurement; Memory; Metabolic; Methods; Mitochondria; Modality; Molecular; Mus; Mutation; Myelin; Neurons; Oligodendroglia; Pathology; Pharmacology; Public Health; Radial; Reporting; Research; Sirolimus; Surrogate Markers; Synapses; Technology; Testing; Therapeutic Uses; Transgenic Mice; Translating; Treatment Efficacy; Validation; Water; abeta accumulation; age related neurodegeneration; arm; base; behavior test; behavioral outcome; brain tissue; cerebrovascular; cognitive function; cohort; density; familial Alzheimer disease; feeding; flexibility; genetic risk factor; glucose metabolism; gray matter; human model; imaging study; improved; in vivo; inhibitor/antagonist; innovation; mouse development; mouse model; multidisciplinary; multimodality; nanoparticle; neuroimaging; neuroinflammation; neuropathology; neurovascular; new technology; novel; object recognition; outcome prediction; overexpression; prevent; tau aggregation; time use; tool; white matter

Project Summary Apolipoprotein ε4 (APOE4) allele is the strongest genetic risk factor for Alzheimer’s disease (AD). Neuroimaging studies in humans have shown that cognitively normal APOE4 carriers develop vascular, metabolic and structural deficits decades before the aggregation of beta-amyloid (Aβ) and neurofibrillary tau tangles. Interventions that can restore these deficits to normal would be critical to potentially prevent the development of AD related neuropathology and cognitive impairment. The rationale of the study is to use the state-of-the-art, in vivo MRI methods to identify a potential intervention, Rapamcyin, for AD prevention in a mouse model that overexpresses human Aβ via 5 familial-AD mutations, and expresses human APOE4 (E4FAD). The central hypothesis is that multi-modal MRI can be used as surrogate markers to assess efficacy of Rapamycin for restoring brain vascular, metabolic, and structural functions in mice that carry APOE4 genes. We will also validate our MRI results by comparison with biochemical assays, and finally compare with behavioral outcomes. The hypothesis will be tested by pursuing three specific aims: 1) Test the hypothesis that Rapamycin restores neurovascular functions; 2) Test the hypothesis that Rapamycin protects neurometabolic functions; and, 3) Test the hypothesis that Rapamycin preserves structural and cognitive functions. The project is innovative because it employs cutting-edge, multi-disciplinary novel technology to focus on early interventions that may become an effective way to prevent AD-induced dementia for APOE4 carriers. The project is significant because with validation, these multimodal MRI methods will dramatically enhance future research for identifying potential therapeutics using animal models in the fields related to AD and other age- related neurodegenerative disorders. We can also translate our approach to future human studies because all the MRI methods used in the proposal are readily able to be used in humans. Because Rapamycin is FDA- approved, the findings from the study will also provide valuable information, and may pave a way, for future Rapamycin clinical trials to prevent dementia for pre-symptomatic APOE4 carriers. !

项目摘要 载脂蛋白ε4（Apolipoprotein ε 4，APOE 4）等位基因是阿尔茨海默病（Alzheimer's disease，AD）最强的遗传危险因子。 人类的神经影像学研究表明，认知正常的APOE 4携带者会发生血管， 在β-淀粉样蛋白（Aβ）和神经元tau蛋白聚集之前数十年， 缠结。能够使这些赤字恢复正常的干预措施对于潜在地防止 AD相关神经病理学和认知损害的发展。研究的基本原理是使用 目前最先进的体内MRI方法，以确定潜在的干预，雷帕霉素，用于预防AD， 通过5种家族性AD突变过表达人Aβ并表达人APOE 4的小鼠模型 （E4FAD）。中心假设是多模态MRI可用作评估疗效的替代标志物 雷帕霉素用于恢复携带APOE 4基因的小鼠的脑血管、代谢和结构功能。 我们还将通过与生化测定的比较来验证我们的MRI结果，并最终与 行为结果该假设将通过追求三个具体目标进行测试：1）测试假设， 雷帕霉素恢复神经血管功能; 2）检验雷帕霉素保护神经代谢的假设 功能;和，3）测试雷帕霉素保留结构和认知功能的假设。项目 是创新的，因为它采用了尖端的，多学科的新技术，专注于早期 这些干预措施可能成为预防APOE 4携带者AD诱导的痴呆的有效方法。的 该项目意义重大，因为通过验证，这些多模式MRI方法将大大提高未来的 在与AD和其他年龄相关的领域中，使用动物模型来确定潜在治疗方法的研究- 相关的神经退行性疾病。我们还可以将我们的方法转化为未来的人类研究，因为所有 在该建议中使用的MRI方法能够容易地用于人类。因为雷帕霉素是FDA- 这项研究的结果也将提供有价值的信息，并可能为未来的研究铺平道路。 雷帕霉素预防症状前APOE 4携带者痴呆的临床试验 !