Innate Immunity Stimulation Effects on Biomarkers, Cognition, and the Vascular Amyloid Proteome in a Squirrel Monkey Model of Sporadic CAA

先天免疫刺激对散发性 CAA 松鼠猴模型中生物标志物、认知和血管淀粉样蛋白组的影响

• 批准号: 10503406
• 负责人: Henrieta Scholtzova
• 金额: $ 84.12万
• 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: 2022-07-15 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10503406
• 关键词: Adjuvant; Age; Agonist; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease pathology; Amyloid; Animals; Autopsy; Behavioral; Biological Assay; Biological Markers; Biological Response Modifiers; Blood; Blood Vessels; Brain; Brain Pathology; Cells; Cerebral Amyloid Angiopathy; Chronic; Clinical; Clinical Trials; Cognition; Cognitive; Complication; Data; Defect; Development; Diffusion; Diffusion Magnetic Resonance Imaging; Disease Progression; Effectiveness; Elderly; Environment; Enzyme-Linked Immunosorbent Assay; Evaluation; FDA approved; Failure; Family; Formalin; Goals; Hepatitis B Vaccines; Human; Image; Immune; Immunohistochemistry; Immunotherapeutic agent; Impaired cognition; Incidence; Individual; Inflammation; Intervention; Label; Lesion; Link; Liquid substance; Macrophage Activation; Magnetic Resonance Imaging; Maps; Mass Spectrum Analysis; Measures; Methods; Microglia; Modeling; Monitor; Monkeys; Natural Immunity; Nerve Degeneration; Paraffin Embedding; Pathogenesis; Pathologic; Pathology; Patients; Peripheral; Phenotype; Play; Primates; Process; Proteins; Proteome; Proteomics; Risk Factors; Role; Safety; Saimiri; Saline; Senile Plaques; Severities; Sporadic Cerebral Amyloid Angiopathy; Stimulus; Structure of choroid plexus; System; TLR9 gene; Techniques; Testing; Therapeutic; Time; Tissue Embedding; Toll-like receptors; Transgenic Mice; Translations; Vascular Diseases; White Matter Hyperintensity; age related; aged; amyloid pathology; biomarker signature; brain tissue; cell type; clinical application; clinically relevant; cognitive benefits; cognitive task; cognitive testing; cohort; coronavirus disease; design; diagnostic biomarker; diagnostic value; imaging biomarker; immunoregulation; improved; in vivo; innovation; insight; laser capture microdissection; magnetic resonance imaging biomarker; mouse model; neuropathology; new therapeutic target; nonhuman primate; pre-clinical; premature; response; screening; social group; tau Proteins; tau-1; trafficking; treatment effect; treatment response; vaccine trial; white matter; white matter change

PROJECT SUMMARY Dysregulation of innate immunity is thought to be a significant contributor to Alzheimer’s disease (AD) pathogenesis. We have focused on harnessing innate immunity via Toll-like receptor 9 (TLR9) to modulate age- related defects in immune cells to counteract AD pathology. Our findings from multiple AD pathology transgenic mouse models provide the first in vivo evidence that stimulation of innate immunity with TLR9 agonist CpG ODN can reduce behavioral deficits and ameliorate all pathological hallmarks of AD. Most current immunotherapeutic trials for AD have been associated with a major complication referred to as amyloid-related imaging abnormalities (ARIA), which is linked to the presence and extent of cerebral amyloid angiopathy (CAA). CAA is present in a majority of individuals with AD, and its severity is an independent risk factor for cognitive decline. Hence, it is critical to develop a therapy effective against CAA without inducing ARIA complications. Additionally, the premature translation of promising transgenic mice data directly to patients has been associated with a very high clinical trial failure rate. Our recent study established that squirrel monkeys (SQMs), an NHP model that develops extensive age-dependent CAA unlike other primates, represent an opportune environment for demonstrating the therapeutic benefits of our immunomodulation using CpG ODN 2006. Here we propose the use of class B CpG 1018, which is currently being tested in clinical trials for a variety of indications. The collective studies are designed to provide a comprehensive portrayal of CpG 1018 efficacy and long-term safety by integrating biofluid biomarker signatures with imaging markers, cognitive measures, in addition to neuropathology correlates. Disease progression and safety will also be monitored by a combination of MRI techniques, which will enable morphometric characterization and screening for ARIA. The utility of a multi-shell diffusion MRI model to follow CpG 1018’s treatment effects in vivo on brain microstructural integrity, especially WM integrity changes, will be validated for the first time. An additional strength of this proposal is the use of our powerful proteomic strategy to unveil the first comprehensive characterization of the CAA and choroid plexus (CP) proteomes in association with disease progression and CpG 1018 intervention. This localized proteomic approach is a preferred method as it combines unbiased mass spectrometry examination with laser capture microdissection to precisely excise defined neuropathological lesions. A further aim of this study is to map involvement of the CP-CSF system in immune cell trafficking in response to CpG 1018. Delineating the CAA and CP protein signatures will advance understanding of CpG 1018’s favorable immunomodulatory capabilities, as well as provide insights into CAA pathogenesis to improve diagnostic capability. Overall, the interventions described here will provide essential preclinical evidence that will enhance CpG 1018’s potential for clinical application.

项目摘要 先天免疫的失调被认为是导致阿尔茨海默氏病的重要原因（AD） 发病。我们专注于通过Toll样受体9（TLR9）来利用先天免疫来调节年龄 免疫细胞中的相关缺陷以抵消AD病理学。我们来自多个AD病理学转基因的发现 小鼠模型提供了第一个体内证据，表明用TLR9激动剂CpG ODN刺激先天免疫力 可以减少行为定义并改善AD的所有病理标志。大多数当前的免疫治疗 AD的试验与称为淀粉样蛋白相关成像异常的主要并发症有关 （ARIA），与脑淀粉样血管病（CAA）的存在和程度有关。 CAA存在于 大多数AD患者及其严重性是认知能力下降的独立危险因素。因此，是 在没有诱导的芳香并发症的情况下开发有效的CAA疗法至关重要。另外， 直接向患者的承诺转基因小鼠数据的过早翻译与非常高有关 临床试验失败率。我们最近的研究表明，松鼠猴（SQMS）是一种发展的NHP模型 与其他素数不同，广泛依赖年龄的CAA代表了证明的机会环境 使用CPG ODN 2006对我们的免疫调节的治疗益处。在这里我们提出使用B类CPG 1018，目前正在临床试验中测试各种适应症。集体研究是 旨在通过整合生物流体来提供CPG 1018效率和长期安全性的全面刻画 除神经病理学相关外，具有成像标记，认知测量值的生物标志物特征。 疾病的进展和安全性也将通过MRI技术的组合来监测，这将使 咏叹调的形态特征和筛选。多壳扩散MRI模型的实用性 CpG 1018在体内的治疗效果对脑微结构完整性，尤其是WM完整性的变化，将是 首次验证。该建议的另一个优势是使用我们强大的蛋白质组学策略 揭示CAA和脉络丛（CP）蛋白质组的首次全面表征 疾病进展和CPG 1018干预。这种局部蛋白质组学方法是首选方法 因为它结合了公正的质谱检查和激光捕获微分解与精确运动 定义的神经病理病变。这项研究的进一步目的是映射CP-CSF系统的参与 免疫细胞运输对CPG 1018的响应。描述CAA和CP蛋白质特征将推进 了解CPG 1018的有利免疫调节能力，并提供有关CAA的见解 提高诊断能力的发病机理。总体而言，此处描述的干预措施将提供 基本的临床前证据将增强CPG 1018的临床应用潜力。