Development and Validation of a Marmoset Model of Late-Onset Alzheimer Disease Based on Tau Seeding

项目名称： 基于Tau接种的晚发性阿尔茨海默病绒猴模型的建立与验证 项目总结/摘要： 阿尔茨海默病（AD）是痴呆症最常见的原因，目前困扰着580万美国人。通过 到2050年，AD患者人数可能达到近1400万。在组织学上，AD的特征在于： β-淀粉样蛋白（Aβ）蛋白片段的细胞外聚集体（斑块）和细胞内 微管相关蛋白过度磷酸化形式的聚集体（神经元缠结，NFT） tau（MAPT）。越来越多的证据表明，Aβ斑块和NFT开始在大脑中积累 在症状出现前几十年。Aβ和tau蛋白表现之间的长时间延迟以及 AD中的记忆丧失和认知下降使得难以使用短寿命动物适当地建模AD 模型，如小鼠。由于年龄和遗传变异是AD的两个最重要的风险因素， 迫切需要开发改进的AD动物模型，该模型包括遗传变异性、衰老和更高的- 更好地与人类保持一致的认知过程。普通的绒猴（Callithrix jacchus）是一种小型的 非人灵长类动物（NHP）的理想准备，以满足这一需求。他们的社交和认知行为 更接近人类。绒猴的平均寿命为12-13年，被认为是8岁 年Aβ斑块和过度磷酸化的tau蛋白自然发生在衰老的绒猴大脑中。发展中 加速与AD病理学标志相关的认知功能减退发作的策略 将导致建立相对于啮齿动物具有改善的翻译潜力的NHP模型 模型本提案的总体目标是开发和验证一种晚发型的诱导绒猴模型 AD.汇聚的临床数据表明，散发性AD的认知功能障碍的严重程度最相关 与NFT的负担。我们假设，向衰老的绒猴的大脑注射tau蛋白， NFT的形成和传播，并加速AD相关疾病谱中损伤的出现。 与疾病进展相关的感觉、运动、认知和非认知表型。我们将测试这个 假设有两个目标。在目标1中，我们将使用来自衰老绒猴的神经元细胞培养物来定量 AD相关病理学在体外的自发存在，并评估tau接种策略的功效 加速NFT的发展，促进神经变性和细胞死亡。在目标2中，我们将 在衰老的绒猴大脑中接种tau蛋白，并对它们进行全面的纵向评估。 tau种子绒猴中AD的功能、行为和临床生物标志物。这项工作将导致 建立一个经过验证的晚发性AD的NHP模型，这在转化研究中将是非常宝贵的， 阐明AD的发病机制，为开发AD的新治疗药物做出贡献。

PROJECT TITLE: Development and Validation of a Marmoset Model of Late-Onset Alzheimer’s Disease Based on Tau Seeding PROJECT SUMMARY/ABSTRACT: Alzheimer’s disease (AD), the most common cause of dementia, currently afflicts 5.8 million Americans. By 2050, the number of people with AD could reach nearly 14 million. Histopathologically, AD is characterized by the formation of extracellular aggregates (plaques) of beta-amyloid (Aβ) protein fragments and intracellular aggregates (neurofibrillary tangles, NFTs) of a hyperphosphorylated form of the microtubule-associated protein tau (MAPT). Increasing evidence indicates that both Aβ plaques and NFTs begin to accumulate in the brain decades before symptoms emerge. The long delay between Aβ and tau manifestation and the onset of memory loss and cognitive decline in AD makes it difficult to properly model AD using short-lived animal models, such as mice. As age and genetic variation are two of the most significant risk factors for AD, there is a critical need to develop improved animal models of AD that incorporate genetic variability, aging, and higher- order cognitive processes that better align with humans. The common marmoset (Callithrix jacchus) is a small non-human primate (NHP) ideally poised to fill this need. They display social and cognitive behaviors that are more similar to those of humans. Marmosets live on average 12-13 years and are considered aged at eight years. Aβ plaques and hyperphosphorylated tau occur naturally in the brain of aging marmosets. Developing strategies to accelerate the onset of cognitive decline related to the presence of pathological hallmarks of AD in marmosets would lead to establishing an NHP model with improved translational potential relative to rodent models. The overall goal of this proposal is to develop and validate an induced marmoset model of late-onset AD. Converging clinical data indicates that the severity of cognitive impairment in sporadic AD correlates best with the burden of NFTs. We hypothesize that injecting the brain of aging marmosets with tau will seed the formation and propagation of NFTs and accelerate the emergence of impairments in a spectrum of AD-related sensory, motor, cognitive and non-cognitive phenotypes associated with disease progression. We will test this hypothesis in two aims. In Aim 1, we will use neuronal cell cultures derived from aging marmosets to quantify the spontaneous presence of AD-related pathology in vitro and evaluate the efficacy of tau seeding strategies in accelerating the development of NFTs and promoting neurodegeneration and cell death. In Aim 2, we will seed the brains of aging marmosets with tau, and perform a comprehensive longitudinal evaluation of functional, behavioral, and clinical biomarkers of AD in the tau-seeded marmosets. This work will lead to the establishment of a validated NHP model of late-onset AD that will be invaluable in translational research to elucidate the pathogenic mechanisms of AD and contribute to developing new therapeutics for AD.