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

项目摘要 载脂蛋白ε4(Apo4)等位基因是阿尔茨海默病(AD)最强的遗传危险因素。 人类的神经成像研究表明，认知正常的APOE4携带者会发生血管病变， 在β-淀粉样蛋白(Aβ)和神经原纤维tau聚集前数十年的代谢和结构缺陷 唐格斯。能够将这些赤字恢复到正常水平的干预措施对于潜在地防止 阿尔茨海默病相关的神经病理和认知损害的发展。这项研究的基本原理是使用 最先进的活体MRI方法，以确定潜在的干预措施，雷帕霉素，以预防AD 通过5个家族性AD突变过表达人Aβ和表达人Apo4的小鼠模型 (E4FAD)。中心假设是多模式MRI可以作为评估疗效的替代标记物 雷帕霉素用于恢复携带APOE4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分析的比较来验证我们的MRI结果，并最终与 行为结果。该假说将通过追求三个具体目标来检验：1)检验假说 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；以及，3)检验雷帕霉素保留结构和认知功能的假设。该项目 是创新的，因为它使用了尖端的、多学科的新颖技术来专注于早期 干预措施可能成为预防APOE4携带者AD诱发痴呆的有效方法。这个 该项目意义重大，因为通过验证，这些多模式MRI方法将极大地增强未来 在与AD和其他年龄相关的领域使用动物模型识别潜在疗法的研究 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 该提案中使用的核磁共振方法很容易用于人类。因为雷帕霉素是FDA- 如果得到批准，研究结果还将提供有价值的信息，并可能为未来铺平道路 雷帕霉素预防无症状载脂蛋白4携带者痴呆的临床试验。 好了！

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. !