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，其定义为大脑中的病理变化， 行为和认知功能改变需要AD的灵长类动物模型，因为它们自然地 概括了老年AD的一些神经病理学特征，而其他模式生物体（即， 啮齿类动物）不。例如，虽然淀粉样蛋白β（Aβ）沉积发生在少数哺乳动物中，但tau蛋白阳性 迄今为止，仅在非常有限的非人类物种中发现了神经元缠结。 此外，老年非人灵长类动物，发展脑淀粉样血管病（CAA），一种神经血管疾病， 在几乎100%的AD患者中发现，并与认知能力下降相关。在此，我们建议 进一步发展松鼠猴作为目前和未来衰老生物学研究的模式物种 AD研究。在R21组件中，我们建议在R21上训练一群生活的松鼠猴。 使用自动认知测试系统（Automated cognitive testing system，简称CET），旨在评估各种认知功能 包括学习记忆和执行控制创造了大量的松鼠猴， CRTOS系统将为动物提供已确定的认知表型，用于临床前研究， 允许检查它们与神经解剖学中潜在的年龄相关差异的关联， 神经病理学和生物标志物数据。在拟议研究的R33部分中，我们将测试 年龄相关的认知变化与血液/CSF生物标志物、神经 组织和完整性以及神经病理学。此外，我们还将测试重复训练对 神经解剖学、神经病理学和AD相关生物标志物的年龄相关变化。具体而言，在年 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 猴子们接受过训练，在这个队列中，20只猴子将接受持续的认知训练， (ACTS+）在第三至五年期间，其余20人将不会接受任何新认知的培训 问（-）。在一个子组的α +和β-猴，我们将获得死后测量， 神经病理学在一组分析中，我们将检验以下指标的纵向变化： 认知及其与（1）从MRI量化的神经组织和完整性变化的关联 扫描和（2）AD相关神经病理学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，我们将比较与年龄相关的变化， 在认知和大脑方面的差异。拟议的研究将全面 填补了我们对松鼠猴衰老和疾病的比较生物学知识的重要空白 并提供关键的翻译洞察这些过程如何有助于CAA和AD的进展 在人类身上。这一信息将为未来使用非人类的AD治疗试验提供关键方向 灵长类动物模型，并提高成功转化为患者的潜力。

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.