A Squirrel Monkey Model of Alzheimer’s Disease: Developing Behavioral, Blood, and CSF Biomarkers

项目摘要 阿尔茨海默病(AD)是一种主要的健康问题，其定义是大脑中产生的病理变化 行为和认知功能的改变。AD的灵长类动物模型是有必要的，因为它们自然地 概括了高龄AD的一些神经病理特征，而其他模式生物(即， 啮齿动物)不会。例如，虽然淀粉样β蛋白(Aβ)沉积在少数哺乳动物身上，但tau阳性 到目前为止，只在非常有限的非人类物种中发现了神经原纤维缠结。 此外，年长的非人灵长类动物会患上脑淀粉样血管病(CAA)，这是一种神经血管 几乎100%的AD患者都有这种情况，并与认知能力下降有关。在这里，我们提议 进一步发展松鼠猴作为当前和未来衰老生物学研究的模式物种 和AD研究。在R21组件中，我们建议在R21组件上训练一群活松鼠猴子 使用旨在评估各种认知功能的自动认知测试系统(ACTS) 包括学习、记忆和执行控制。创造了一大群松鼠猴子，在 ACTS系统将为动物提供已建立的认知表型，用于临床前研究和 允许检查它们与潜在的与年龄相关的神经解剖学上的差异， 神经病理和生物标记物数据。在拟议研究的R33部分中，我们将测试 增龄性认知改变与血液/脑脊液生物标志物、神经功能的关系 组织和完整性以及神经病理学。此外，我们将测试ACTS培训对 神经解剖学、神经病理学和AD相关生物标志物的增龄相关变化。具体地说，在这些年里 3至5，我们将获得40名老年人和老年人的磁共振图像(MRI)和生物样本 猴子接受过ACTS系统的训练。有了这个队列，20只猴子将接受持续的认知训练 (ACTS+)在3至5年级期间，其余20人将不接受任何新认知的培训 问(使徒行传-)。在ACTS+和ACTS-猴子的子集中，我们将获得 神经病理学。在ACTS队列中的一组分析中，我们将测试以下方面的纵向变化 认知及其与(1)MRI量化的神经组织和完整性变异的关系 扫描和(2)AD相关神经病理的几个关键生物标志物。此外，为了检查是否 认知刺激减缓正常的大脑衰老过程，我们将比较年龄相关的变化在 认知和大脑之间的行为+和行为-猴子。拟议的研究，整体而言，将 填补了我们对松鼠猴子衰老和疾病的比较生物学知识的一个重要空白 并提供关键的翻译洞察，了解这些流程如何促进CAA和AD的发展 在人类身上。这一信息将为未来使用非人类进行的AD治疗试验提供关键方向 灵长类动物模型，并增强向患者成功翻译的潜力。

Project Summary Alzheimer’s disease (AD) is a major health concern defined by pathologic changes in the brain that produce altered behavior and cognitive function. There is a need for primate models of AD because they naturally recapitulate some neuropathological features of AD with advanced age whereas other model organisms (i.e., rodents) do not. For instance, while amyloid-beta (Aβ) deposition occurs in a few mammals, tau-positive neurofibrillary tangles have only been identified in a very limited nonhuman species studied to date. Additionally, elderly nonhuman primates, develop cerebral amyloid angiopathy (CAA), a neurovascular condition found in almost 100% of AD patients and associated with cognitive decline. Here, we are proposing to further develop squirrel monkeys as a model species for current and future studies on the biology of aging and AD research. In the R21 component, we propose to train a cohort of group living squirrel monkeys on the use of an automated cognitive testing system (ACTS) that is designed to assess a variety of cognitive functions including learning, memory and executive control. Creating large cohorts of squirrel monkeys trained on the ACTS system will provide animals with established cognitive phenotypes for use in preclinical studies and allow for examining of their association with potential age-related differences in neuroanatomical, neuropathological and biomarker data. In the R33 component of the proposed studies, we will test for associations between age-related changes in cognition and measures of blood/CSF biomarkers, neural organization and integrity and neuropathology. Additionally, we will test for the effect of ACTS training on aged related changes in neuroanatomy, neuropathology and AD-related biomarkers. Specifically, during Years 3 to 5, we will obtain magnetic resonance images (MRI) and biological samples from 40 elderly and geriatric monkeys trained on the ACTS system. With this cohort, 20 monkeys will receive continued cognitive training (ACTS+) during year 3 to 5 while the remaining 20 individuals will not receive training on any new cognition asks (ACTS-). In a subset of ACTS+ and ACTS- monkeys, we will obtain postmortem measures of neuropathology. In one set of analyses within the ACTS cohort, we will test for longitudinal changes in cognition and their association with variation in (1) neural organization and integrity quantified form MRI scans and (2) several key biomarkers of AD-related neuropathology. Additionally, to examine whether cognitive stimulation slows down the normal brain aging process, we will compare age-related changes in cognition and the brain between the ACTS+ and ACTS- monkeys. The proposed studies, in their entirety, will fill an important gap in our knowledge about the comparative biology of aging and disease in squirrel monkeys and provide critical translational insight into how those processes contribute to the progression of CAA and AD in humans. This information will provide crucial direction for future AD therapeutic trials using nonhuman primate models and enhance the potential of successful translation to patients.