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

项目摘要 先天免疫失调被认为是阿尔茨海默病（AD）的重要原因 发病机制我们专注于通过Toll样受体9（TLR 9）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。我们的发现来自多种AD病理转基因 小鼠模型提供了第一个体内证据，即用TLR 9激动剂CpG ODN刺激先天免疫 可以减少行为缺陷并改善AD的所有病理特征。最新免疫学 AD的临床试验与淀粉样蛋白相关的影像学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 AD是大多数AD患者的常见病，其严重程度是认知功能下降的独立危险因素。因此， 关键是要开发一种有效的治疗CAA，而不诱导ARIA并发症。另夕h 过早地将有希望的转基因小鼠数据直接翻译给患者， 临床试验失败率我们最近的研究确定，松鼠猴（SQM），一种NHP模型， 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 使用CpG ODN的免疫调节的治疗益处2006。在此，我们建议使用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，全面描述CpG 1018的功效和长期安全性 除了神经病理学相关性之外，生物标志物签名与成像标志物、认知测量。 还将通过MRI技术的组合监测疾病进展和安全性，这将使 ARIA的形态测定表征和筛选。多壳层扩散MRI模型的实用性 CpG 1018在体内对脑微结构完整性，特别是WM完整性变化的治疗作用将被证实。 第一次验证。这个建议的另一个优点是使用了我们强大的蛋白质组学策略 揭示CAA和脉络丛（CP）蛋白质组相关的第一个全面特征 疾病进展和CpG 1018干预。这种定位蛋白质组学方法是一种优选的方法 因为它结合了无偏质谱检测和激光捕获显微切割， 明确的神经病理学病变。本研究的另一个目的是绘制CP-CSF系统参与 免疫细胞运输响应于CpG 1018。描绘CAA和CP蛋白特征将推进 了解CpG 1018有利的免疫调节能力，并提供对CAA的见解 发病机制，以提高诊断能力。总的来说，本文所述的干预措施将提供 重要的临床前证据，将提高CpG 1018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.