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.

项目名称： 基于Tau种子法的晚发性阿尔茨海默病模型的建立与验证 项目摘要/摘要： 阿尔茨海默病(AD)是导致痴呆症的最常见原因，目前困扰着580万美国人。通过 到2050年，阿尔茨海默病患者可能达到近1400万人。从组织病理学上看，AD的特征是 β-淀粉样蛋白(A-β)片段胞外聚集体(斑块)和胞内聚集体(斑块)的形成 一种高度磷酸化形式的微管相关蛋白的聚集体(神经原纤维缠结，NFT) 牛磺酸(MAPT)。越来越多的证据表明，Aβ斑块和NFT都开始在大脑中积聚 在症状出现前几十年。β和Tau表现之间的长时间延迟与心绞痛的发病 阿尔茨海默病的记忆丧失和认知功能减退使得使用短暂的动物建立适当的阿尔茨海默病模型很困难 模型，如老鼠。由于年龄和遗传变异是阿尔茨海默病的两个最重要的风险因素，因此 迫切需要开发改进的AD动物模型，包括遗传变异性、衰老和更高的- 让认知过程更好地与人类保持一致。常见的绒猴(Callithrix Jacchus)是一种小型的 非人灵长类(NHP)最适合满足这一需求。它们表现出的社会和认知行为是 更接近于人类。绒猴的平均寿命为12-13年，被认为是8岁。 好几年了。β斑块和过度磷酸化的tau自然地出现在老化的绒猴的大脑中。发展中 与阿尔茨海默病的病理特征相关的加速认知功能下降的策略 将导致建立相对于啮齿动物具有更好翻译潜力的NHP模型 模特们。这项提案的总体目标是开发和验证晚发性绒猴模型。 广告。聚合的临床数据表明，散发性阿尔茨海默病患者认知损害的严重程度与 背负着NFTs的重担。我们假设，给老化的绒猴的大脑注射tau会使 NFTs的形成和传播，并加速AD相关谱系中损害的出现 与疾病进展相关的感觉、运动、认知和非认知表型。我们将对此进行测试 假设有两个目的。在目标1中，我们将使用来自老化绒猴的神经细胞培养来量化 阿尔茨海默病相关病理的体外自发存在及tau接种策略的疗效评价 促进NFTs的发展，促进神经退行性变和细胞死亡。在目标2中，我们将 在老化的绒猴脑中植入tau，并进行全面的纵向评估 Tau种子猴阿尔茨海默病的功能、行为和临床生物标志物。这项工作将导致 建立一个有效的晚发性AD的NHP模型，这将在翻译研究中具有非常重要的价值 阐明阿尔茨海默病的发病机制，有助于开发治疗阿尔茨海默病的新疗法。