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

基于 Tau 接种的晚发性阿尔茨海默病狨猴模型的开发和验证

• 批准号: 10468141
• 负责人: Afonso C Silva
• 金额: $ 110.56万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-15 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10468141
• 关键词: Age; Aging; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease patient; Alzheimer' s disease risk; Alzheimer' s disease therapeutic; Alzheimer’s disease biomarker; American; Amyloid beta-Protein; Animal Model; Behavior; Behavioral; Biological Markers; Biopsy; Blood - brain barrier anatomy; Brain; Callithrix; Callithrix jacchus jacchus; Cell Culture Techniques; Cell Death; Cerebrovascular Circulation; Clinical; Clinical Data; Clinical assessments; Cognitive; Data; Dementia; Development; Disease Progression; Evaluation; Female; Fibroblasts; Future; Genetic; Genetic Variation; Goals; Hippocampus (Brain); Human; Image; Impaired cognition; Impairment; In Vitro; Injections; Late Onset Alzheimer Disease; Lead; Light; MAPT gene; Magnetic Resonance Imaging; Maps; Measures; Memory Loss; Metabolism; Modeling; Motor; Mus; Nerve Degeneration; Neurofibrillary Tangles; Neurons; Pathogenicity; Pathologic; Pathology; Persons; Phenotype; Plasma; Positron-Emission Tomography; Protein Fragment; Recombinant adeno-associated virus (rAAV); Rodent Model; Seeds; Senile Plaques; Sensory; Serotyping; Severities; Skin; Staging; Symptoms; Testing; Time; Translational Research; Validation; Work; aged; aging brain; base; behavior test; clinical biomarkers; cognitive process; cognitive testing; cohort; comparative efficacy; cytokine; efficacy evaluation; entorhinal cortex; experimental study; extracellular; hyperphosphorylated tau; improved; in vivo evaluation; intravenous administration; male; nerve stem cell; neurofibrillary tangle formation; neurofilament; nonhuman primate; novel therapeutics; social; spatiotemporal; stem cell differentiation; tau Proteins; tau aggregation; transcriptomics; translational potential; translational study

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.

项目标题： 基于tau播种 项目摘要/摘要： 阿尔茨海默氏病（AD）是痴呆症最常见的原因，目前遭受了580万美国人的困扰。经过 2050年，广告人数可能达到近1400万。在组织病理学上，AD的特征是 β-淀粉样蛋白（Aβ）蛋白质片段和细胞内细胞外聚集体（斑块）的形成 微磷酸化形式的微管相关蛋白的聚集体（神经原纤维缠结，NFTS） tau（mapt）。越来越多的证据表明Aβ斑块和NFT都开始在大脑中积累 症状出现前几十年。 Aβ和TAU表现之间的长延迟以及 AD的记忆力丧失和认知能力下降使得很难使用短暂的动物正确对AD进行建模 模型，例如小鼠。由于年龄和遗传变异是AD的两个最重要的危险因素，因此 建立改进的AD动物模型的迫切需要，该模型融合了遗传变异性，衰老和较高的动物模型 订购认知过程，以更好地与人类保持一致。普通的marmoset（callithrix jacchus）很小 非人类灵长类动物（NHP）理想中毒以满足这一需求。他们表现出社会和认知行为 与人类更相似。摩尔马人平均生活12-13岁，被认为年龄八岁 年。 Aβ斑块和高磷酸化的tau天然发生在衰老的果mos虫的大脑中。发展 加速与AD病理标志有关的认知下降开始的策略 在摩尔果中，将导致建立具有相对于啮齿动物的翻译潜力提高的NHP模型 型号。该提案的总体目标是开发和验证诱发的玛格塞特模型 广告。融合临床数据表明，零星广告中认知障碍的严重程度与最佳相关 随着NFT的燃烧。我们假设向tau注射衰老的果mos子的大脑会播种 NFT的形成和传播，并加速了与广告相关的障碍的出现 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 两个目标的假设。在AIM 1中，我们将使用衍生自衰老果moset的神经元细胞培养物来量化 在体外具有赞助广告相关的病理，并评估tau播种策略的效率 在AIM 2中，我们将 用tau播种老化的摩尔奶酪的大脑，并对 AD的功能性，行为和临床生物标志物在tau种子的果果中。这项工作将导致 建立经过验证的晚期广告的NHP模型，在翻译研究中将是无价的 阐明AD的致病机制，并有助于开发AD的新疗法。