National Swine Resource and Research Center 1

项目总结/摘要 本提案的总体目标是研究APP和PSEN 1在促进 阿尔茨海默病（AD）的研究。阿尔茨海默病是痴呆症的主要原因， 影响了10%的美国人口不幸的是，目前没有治疗选择，可以扭转的轨迹， 疾病存在。AD的小鼠模型对于确定这种疾病的潜在病理生理学至关重要。 然而，这些模型往往不能概括人类状况的所有症状，这表明， 需要AD的动物模型来促进我们对这种疾病的理解并加速药物发现 努力猪是容易获得的，并且由于其解剖学和生物学特性而被认为是极好的生物医学模型。 与人类的生理相似性此外，与啮齿动物模型相比，猪的大脑更相似 它可以执行更复杂的认知任务，更好地模拟人类行为。 最近关于淀粉样斑块对AD进展的重要性的有争议的报道表明， 研究独立于淀粉样斑块的APP和PSEN 1的潜在作用。因为特定 APP和PSEN 1的多态性与早发性AD即家族性阿尔茨海默病的患病率有关 了解APP和PSEN 1在AD发病机制中的作用，有助于阐明AD的发病机制。在研究 先前的NOT-AG-20-034，我们已经产生了携带AD的APP敲除猪和PSEN 1突变猪 相关等位基因（ΔE9）。研究APP-/-、PSEN 1 +/ΔE9和APP-/-PSEN 1 +/ΔE9猪的表型， 揭示了APP和PSEN 1的新作用，它们与大脑中的淀粉样蛋白存款无关。据我们所 知识，我们提出的工作将提供一个新的大型动物模型，从一个新的解剖AD的发病机制， perspective.我们提出两个目标。在目的1中，我们将从细胞水平研究AD猪模型的表型。 和生化水平。将在6-8月龄时收集来自猪的脑，并且在细胞中观察AD的体征。 和分子水平上进行探索。在目标2中，我们将通过使用MRI对猪模型的大脑进行成像， 基因改造导致的潜在萎缩成像工作将使我们能够监测AD的迹象 这些猪模型的进展，也有助于我们优化猪脑成像的方法。常规 小鼠AD模型确实捕获了一些AD症状;然而，由于生理学和脑大小的差异， 模型的研究结果很少被转移到临床。反映表型的多种动物模型 人类AD患者的研究结果应该是非常宝贵的，以设计新的补救措施，并将研究结果转化为临床。 在这里，我们建议通过使用新的猪模型来研究APP和PSEN 1在AD进展中的作用。我们 有专业知识，以完成拟议的实验在拨款的时间表和利用猪模型 对于AD可以作为一种新的资源，以生物医学界，并有助于促进我们的理解， 这种主要神经退行性疾病的潜在治疗方法。

Project Summary/Abstract The overall goal of this proposal is to examine the unique role of APP and PSEN1 for progression of the Alzheimer's disease (AD) by using novel pig models. Alzheimer's disease is the leading cause of dementia and affects 10% of the U.S. population. Unfortunately, currently no treatment option that can reverse trajectory of the disease exists. Mouse models of AD have been critical to identify the underlying pathophysiology of this disorder. However, these models often do not recapitulate all symptoms of the human condition, indicating that additional animal models of AD are needed to facilitate our understanding of this disorder and accelerate drug discovery efforts. Pigs are readily available and are considered to be an excellent biomedical model due to anatomical and physiological similarities to humans. In addition, in comparison to rodent models, pigs have a more similar brain structure to humans and can perform more complicated cognitive tasks that better model human behavior. Recent controversial reports on the importance of amyloid plaques for the progression of AD suggest the need to investigate potential role of APP and PSEN1 that are independent of amyloid plaques. Because specific polymorphisms of APP and PSEN1 are connected to the prevalence of early onset AD, i.e. Familial Alzheimer's disease, understanding the roles of APP and PSEN1 could elucidate pathogenesis of AD. While working on the previous NOT- AG-20-034, we have generated APP knockout pigs and PSEN1 mutant pigs carrying AD associated allele (ΔE9). Investigating the phenotype of APP-/-, PSEN1+/ΔE9, and APP-/-PSEN1+/ΔE9 pigs should reveal novel roles of APP and PSEN1 that are not linked to the amyloid deposit in brain. To the best of our knowledge, our proposed work will offer a novel large animal model to dissect pathogenesis of AD from a new perspective. We propose two aims. In Aim 1, we will investigate the phenotype of AD pig models at the cellular and biochemical level. Brain from the pigs will be collected at 6-8 months of age and signs of AD at the cellular and molecular level will be explored. In Aim 2, we will image the brain of the pig models by using MRI to follow potential atrophy caused by the genetic modifications. The imaging work will allow us to monitor signs of AD progression in these pig models and also help us optimize approaches to image the pig brain. Conventional mouse AD models do capture some AD symptoms; however, due to differences in physiology and size of brain, it is rare that findings from the models are transferred to the clinic. Diverse animal models reflecting phenotypes of human AD patient should be invaluable to design novel remedies and translate the findings into the clinic. Here, we propose to study the role of APP and PSEN1 for the progression of AD by using novel pig models. We have expertise to complete the proposed experiment within the grant timeframe and the utilization of pig models for AD can serve as a novel resource to the biomedical community and help advance our understanding and potential treatment of this major neurodegenerative disorder.