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 阿尔茨海默氏病（AD）是全球痴呆症的最常见原因，没有高效的疾病 - 修改治疗。从转基因小鼠完成的研究直接向AD患者完成的研究过早跳跃 被认为是绝大多数临床试验失败的重要原因之一。潜力 通过测试非人类隐私的有希望的治疗概念，可能会增强对人类的转换性 （NHP），更紧密地概括了AD的神经病理特征。我们最近的研究支持 松鼠猴（SQMS），新热带小学，与其他NHP不同，它会发展出广泛的大脑淀粉样蛋白 所有老年动物的血管病（CAA），用于验证我们的免疫调节的治疗潜力 计划用于人类使用的干预措施。 CAA几乎在所有广告案件中都没有得到治疗，并且 促进更快的认知下降。当前的AD免疫治疗试验的主要并发症是 淀粉样蛋白相关的成像异常（ARIA），与CAA的存在有关；因此突出 SQM中的CAA强调了该模型用于AD和痴呆症研究的重要性。这 此处提出的集体研究旨在对驾驶过程进行全面评估 通过将生物流体生物标志物轨迹与成像标记和认知能力整合到AD和CAA的进展 除了SQMS中死后脑病理学特征外，还采取了措施。我们打算纵向评估年龄 - 使用创新的自动认知测试系统（ACT）实施的认知相关变化 两个不同的社会生活SQM。此外，疾病进展将由 MRI技术的组合，能够形态计量学表征，筛选微射击和 白质超强度。大脑微观结构完整性，尤其是白质（WM）的完整性变化，将会变化 通过在这种易于攻击的独特模型中使用多壳扩散MRI的生物物理模型来检查 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基本见解。也是SQM 提供一个宝贵的机会来确定定义CAA沉积物的蛋白质特征。因此，我们提出 CAA蛋白质组在不同的SQM中的第一个完整表征，表现出轻度和 使用我们公认的局部蛋白质组学方法，严重的CAA病理学。我们蛋白质组学的力量 策略是无偏质谱检查与激光捕获显微解剖的组合 精确消除并表征定义的神经病理病变。总体而言，我们相信深入的刻画 该NHP模型将为CAA发病机理的未来翻译研究提供关键基础， 为了提高诊断能力并提高创新疗法。