Characterization of Biomarkers and the Vascular Amyloid Proteome in a Non-human Primate Model of Alzheimer’s Disease

项目总结 阿尔茨海默病(AD)是全球最常见的痴呆症病因，没有高度有效的疾病- 修改治疗方法。从转基因小鼠中完成的研究过早地跳到了AD患者身上 被认为是绝大多数临床试验失败的重要原因之一。潜在的 在非人类灵长类动物中测试有希望的治疗概念可能会增强对人类的可译性 (NHPS)，更能概括AD的神经病理特征。我们最近的研究支持使用 松鼠猴(Sqm)是一种新热带灵长类动物，与其他NHP不同，它会发展成广泛的大脑淀粉样蛋白 所有老年动物的血管病变(CAA)，以验证我们的免疫调节剂的治疗潜力 为人类使用而计划的干预。几乎所有AD病例中都存在CAA，但目前尚无治疗方法 促进更快的认知能力下降。目前AD免疫治疗试验的主要并发症是 淀粉样蛋白相关成像异常(ARIA)，与CAA的存在有关；因此显著 在SQMS中的CAA研究强调了推动这一模型用于AD和痴呆症研究的重要性。这个 这里提出的集体研究旨在提供对驱动过程的全面评估 结合生物体液生物标志物轨迹、影像标志物和认知功能的AD和CAA研究进展 措施，除死后脑病理特征外，SQM。我们打算纵向评估年龄- 使用创新的自动化认知测试系统(ACTS)在认知方面的相关变化 两个不同年龄段的社交生活Sqm。此外，疾病的进展将由一个 MRI技术的组合能够进行形态测量特征、微小出血的筛查和 脑白质高信号。大脑微结构完整性，特别是白质(WM)完整性的变化，将 通过利用多壳扩散核磁共振的生物物理模型进行检查，在这一独特的模型中易患 脑血管病理学。进一步了解微结构WM改变之间的联系， 认知功能和病理相关因素将为临床实践提供必要的见解。Sqms还 提供了一个宝贵的机会来确定定义CAA沉积的蛋白质特征。因此，我们建议 首次在不同的SQM组中对CAA蛋白质组进行了完整的表征，显示出温和和 严重的CAA病理，利用我们成熟的局部蛋白质组学方法。我们蛋白质组的力量 策略是将无偏的质谱学检查与激光捕获显微解剖相结合 以精确切除和描述明确的神经病理损害。总体而言，我们认为深入的描绘 这一NHP模型的建立将为未来CAA发病机制的翻译研究提供重要的基础。 以提高诊断能力，推进创新治疗。

PROJECT SUMMARY Alzheimer’s disease (AD) is the most common cause of dementia worldwide with no highly effective disease- modifying treatment. A premature jump from studies completed in transgenic mice directly to AD patients has been cited as one of the significant reasons for failure of the vast majority of clinical trials. The potential for translatability to humans is likely enhanced by testing promising therapeutic concepts in non-human primates (NHPs), which more closely recapitulate neuropathological features of AD. Our recent study supports the use of squirrel monkeys (SQMs), neotropical primates which unlike other NHPs develops extensive cerebral amyloid angiopathy (CAA) in all aged animals, for validating the therapeutic potential of our immunomodulatory intervention planned for human use. CAA, for which there is no treatment, is present in nearly all AD cases and promotes more rapid cognitive decline. The major complications in current immunotherapeutic trials for AD are amyloid-related imaging abnormalities (ARIA), which are linked to the presence of CAA; hence the prominence of CAA in SQMs underlines the importance of advancing this model for use in AD and dementia research. The collective studies proposed here are designed to provide a comprehensive assessment of the processes driving progression of AD and CAA by integrating biofluid biomarker trajectories with imaging markers and cognitive measures, in addition to postmortem brain pathology features in SQMs. We intend to longitudinally evaluate age- related changes in cognition using an innovative Automated Cognitive Testing System (ACTS) implemented in two different-aged cohorts of socially-living SQMs. Moreover, disease progression will be monitored by a combination of MRI techniques enabling morphometric characterization, screening for microhemorrhages, and white matter hyperintensities. Brain microstructural integrity, especially white matter (WM) integrity changes, will be examined by utilizing a biophysical model of multi-shell diffusion MRI in this unique model vulnerable to cerebrovascular pathology. Further understanding of the association between microstructural WM alterations, cognitive function, and pathological correlates will provide essential insights for clinical practice. SQMs also present a valuable opportunity to identify the protein signature that defines CAA deposits. Therefore, we propose the first complete characterization of the CAA proteome across different groups of SQMs exhibiting mild and severe CAA pathology, utilizing our well-established localized proteomic approach. The power of our proteomic strategy is the combination of an unbiased mass spectrometry examination with laser capture microdissection to precisely excise and characterize defined neuropathological lesions. Overall, we believe the in-depth portrayal of this NHP model will provide a critical foundation for future translational research on the pathogenesis of CAA, in order to improve diagnostic capability and advance innovative therapies.