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

项目总结 先天免疫失调被认为是阿尔茨海默病(AD)的一个重要因素 发病机制。我们一直专注于通过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，以对抗AD的病理。我们在多种AD病理转基因研究中的发现 小鼠模型首次提供了TLR9激动剂CpG ODN刺激天然免疫的体内证据 可以减少行为缺陷，改善AD的所有病理特征。最新的免疫疗法 治疗阿尔茨海默病的试验与一种称为淀粉样蛋白相关成像异常的主要并发症有关 (ARIA)，这与脑淀粉样血管病(CAA)的存在和程度有关。CAA存在于 大多数AD患者，其严重程度是认知功能下降的独立危险因素。因此，它是 开发一种在不引发ARIA并发症的情况下有效对抗CAA的治疗方法至关重要。此外， 过早地将有希望的转基因小鼠数据直接翻译给患者与非常高的 临床试验失败率。我们最近的研究建立了松鼠猴子(SQM)，一种NHP模型，它开发了 与其他灵长类动物不同，广泛的年龄依赖性CAA代表了一个展示 我们使用CpG ODN 2006进行免疫调节的治疗益处。在这里，我们建议使用B类CpG 1018，目前正在进行各种适应症的临床试验。集体学习是 旨在通过整合生物流体提供CpG 1018疗效和长期安全性的全面描述 生物标记物签名与成像标记物、认知测量以及神经病理学相关。 疾病的进展和安全性也将通过MRI技术的组合进行监测，这将使 ARIA的形态特征和筛选。多层扩散磁共振成像模型的应用 CPG1018‘S体内治疗对脑微结构完整性的影响，尤其是对西药完整性的影响 首次验证。这一提议的另一个优势是使用了我们强大的蛋白质组学策略 首次揭示CAA和脉络丛(CP)相关蛋白质组的全面特征 疾病进展和CpG1018干预。这种定位的蛋白质组学方法是首选的方法。 因为它结合了无偏质谱学检查和激光捕获显微解剖来精确切除 明确的神经病理损害。本研究的另一个目的是定位慢性粒细胞集落刺激因子系统的参与。 CpG 1018应答的免疫细胞转运。描绘CAA和CP蛋白特征将取得进展 了解CpG1018‘S良好的免疫调节能力，以及对CAA的洞察 发病机制，提高诊断能力。总体而言，这里描述的干预措施将提供 重要的临床前证据，将增强CpG1018‘S的临床应用潜力。

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.