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

阿尔茨海默病非人灵长类动物模型中生物标志物和血管淀粉样蛋白组的表征

• 批准号: 10433252
• 负责人: Henrieta Scholtzova
• 金额: $ 22.74万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-02-01 至 2024-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10433252
• 关键词: Aging; Agonist; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease pathology; Alzheimer' s disease patient; Alzheimer' s disease therapeutic; Alzheimer' s disease therapy; Amyloid; Amyloidosis; Animal Model; Animals; Automobile Driving; Autopsy; Biological Assay; Biological Markers; Biology of Aging; Blood; Blood Vessels; Brain; Brain Pathology; Cerebral Amyloid Angiopathy; Cerebrovascular Disorders; Clinical Trials; Cognition; Cognitive; Comparative Biology; Cross-Sectional Studies; Data; Dementia; Deposition; Development; Diffusion Magnetic Resonance Imaging; Disease; Disease Progression; Effectiveness; Elderly; Environment; Enzyme-Linked Immunosorbent Assay; Exhibits; Failure; Formalin; Foundations; Future; Goals; Human; Image; Imaging Techniques; Immunohistochemistry; Immunotherapeutic agent; Impaired cognition; Individual; Inflammation; Innovative Therapy; Intervention; Knowledge; Label; Learning; Lesion; Link; Liquid substance; Longitudinal Studies; Magnetic Resonance Imaging; Maps; Mass Spectrum Analysis; Measures; Memory; Modeling; Monitor; Mus; Nerve Degeneration; Paraffin Embedding; Pathogenesis; Pathologic; Pathology; Patients; Peripheral; Primates; Process; Process Assessment; Proteins; Proteome; Proteomics; Research; Risk Factors; Safety; Saimiri; Senile Plaques; Severities; System; TLR9 gene; Techniques; Testing; Therapeutic; Therapeutic Agents; Therapeutic Trials; Tissue Embedding; Tissues; Training; Transgenic Mice; Translational Research; Translations; White Matter Hyperintensity; age related; aged; biomarker signature; biophysical model; brain tissue; cell type; cerebrovascular pathology; clinical practice; cognitive function; cognitive task; cognitive testing; cohort; design; diagnostic biomarker; diagnostic value; executive function; follow-up; human disease; imaging biomarker; immunoregulation; improved; in vivo imaging; innovation; insight; laser capture microdissection; magnetic resonance imaging biomarker; neuropathology; nonhuman primate; novel; novel diagnostics; novel therapeutics; premature; screening; social; social group; tau Proteins; tau-1; therapeutic evaluation; therapeutic target; therapy outcome; white matter; white matter change

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.

项目摘要 阿尔茨海默病（AD）是全球痴呆症的最常见原因，没有高效的疾病- 改性处理从转基因小鼠直接到AD患者的研究过早跳跃， 被认为是绝大多数临床试验失败的重要原因之一。的潜力 通过在非人类灵长类动物中测试有前途的治疗概念， （NHPs），其更紧密地概括AD的神经病理学特征。我们最近的研究支持使用 松鼠猴（SQM），新热带灵长类动物，与其他NHP不同， 血管病（CAA），用于验证我们的免疫调节剂的治疗潜力。 计划用于人类的干预措施。CAA，没有治疗方法，几乎存在于所有AD病例中， 会加速认知能力的下降目前AD免疫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， CAA在SQMS中的应用强调了推进该模型用于AD和痴呆研究的重要性。的 这里提出的集体研究旨在提供一个全面的评估过程， 通过整合生物流体生物标志物轨迹与成像标志物和认知功能， 措施，除了死后的脑病理学特征在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（Automated Cognitive Testing System，简称CITS）， 两组不同年龄的社交生活SQM。此外，疾病进展将通过 MRI技术的组合，能够进行形态学表征，筛选微血管， 白色物质高信号。脑微结构完整性，特别是白色物质（WM）完整性变化， 通过利用多壳扩散MRI的生物物理模型进行检查，在这种独特的模型中， 脑血管病理学进一步了解微结构WM改变之间的关联， 认知功能和病理相关性将为临床实践提供必要的见解。SQM也 提供了一个宝贵的机会，以确定蛋白质签名，定义CAA存款。所以我们提出 CAA蛋白质组的第一个完整的表征在不同的SQM组表现出温和的， 严重的CAA病理，利用我们完善的本地化蛋白质组学方法。我们的蛋白质组学的力量 一种策略是将无偏质谱检测与激光捕获显微切割相结合 精确切除和表征确定的神经病理学病变。总的来说，我们认为深入的描述 该NHP模型的建立将为CAA发病机制的未来转化研究提供重要基础， 以提高诊断能力和推进创新疗法。