Elucidating the Role of Endothelial Dysfunction in Alzheimer Disease: Towards A New Data-Driven Disease Model

项目摘要 ≥90%阿尔茨海默病(AD)患者脑内皮细胞结构和功能的改变 在没有脑血管疾病或淀粉样血管病的情况下。尽管它很普遍，但内皮细胞的作用 由于缺乏可靠的内皮细胞，AD发病机制中的功能障碍还没有得到充分的研究 生物标志物。我们已经确定了一组新的内皮生物标志物，其大脑核糖核酸(RNA)和 与对照组相比，AD患者的脑脊液(CSF)蛋白水平发生了显著变化。激动人心的预赛 数据表明，这些蛋白有望成为脑内皮细胞的新的诊断和预后生物标志物。 阿尔茨海默病患者的功能障碍与认知和放射学结果密切相关。重要的是，我们的初选 AD模型提示内皮功能障碍是淀粉样蛋白之前的早期病理基础 还有陶。我们在这里建议进行第一个深入的全面的内皮细胞翻译研究 阿尔茨海默病的功能障碍。在这项研究中，我们将利用蛋白质组学和转录组学来检测脑脊液蛋白和脑 这些血管内皮细胞标记物在3个特征良好的晚期散发性大的纵向队列中的RNA水平 AD、健康对照组和非AD痴呆患者(合并n&gt；3400人)，他们已经被跟踪20-25年，并且 我们为他们提供了详细的纵向认知、脑脊液、磁共振成像(包括ASL、FLAIR、 和DTI)、淀粉样正电子发射断层扫描(Amyloid-PET)和tau-PET成像数据。在目标1中，我们将 检测脑脊液内皮细胞标记物在AD中的诊断和预后作用及其预测能力 随着时间的推移，认知能力下降和大脑萎缩，与淀粉样蛋白和tau无关。我们还将描述 内皮功能障碍与脑脊液和/或淀粉样蛋白成像标记物的基线和纵向相关性， Tau、炎症和神经元/突触损伤的20-25年的随访，包括10-15年前的 症状出现。在目标2中，我们将在我们的横截面队列中利用基于事件的建模(EBM；目标2A 和我们纵向队列中的多因素数据驱动分析(MFDDA；目标2B)，以提出新的数据驱动 AD的预测模型，它将阐明液体和成像AD标志物的时间顺序以及 AD成像标记物(脑血流、淀粉样蛋白和tau-PET以及脑萎缩)的时空进展 在症状出现前超过10-15年的37个大脑区域。蛋白质组的功能途径分析 来自我们的队列和其他人的RNA-seq数据将确定内皮功能障碍的新机制 导致神经变性，并影响突触可塑性、轴突修复和异常蛋白质 AD中的聚集(目标2C)。通过深入的多组学分析内皮功能障碍和 整合来自大型特征良好的纵向多种族AD队列的多模式数据，我们的目标是 提出一种新的疾病模型，这将是第一个将内皮功能障碍纳入AD范式的疾病模型 并将捕捉到淀粉样蛋白和tau以外的AD的分子和病理异质性。由此得出的结论 这项研究将为AD药物开发提供新的疾病机制和新的分子靶点。

Project Abstract Structural and functional alterations in brain endothelium are observed in ≥90% of Alzheimer Disease (AD) brains in the absence of cerebrovascular disease or amyloid angiopathy. Despite its prevalence, the role of endothelial dysfunction in AD pathogenesis has not been adequately investigated due to the absence of reliable endothelial biomarkers. We have identified a novel panel of endothelial biomarkers whose brain ribonucleic acid (RNA) and cerebrospinal fluid (CSF) protein levels are significantly altered in AD compared to controls. Exciting preliminary data suggest that these proteins offer promise as novel diagnostic and prognostic biomarkers of brain endothelial dysfunction and strongly correlate with cognitive and radiological outcomes in AD. Importantly, our preliminary AD models suggest that endothelial dysfunction is an early pathological substrate which may precede amyloid and tau. We here propose to conduct the first in-depth comprehensive translational study of endothelial dysfunction in AD. In this study, we will utilize proteomics and transcriptomics to measure CSF protein and brain RNA levels of these endothelial markers in 3 large well-characterized longitudinal cohorts of late-onset sporadic AD, healthy controls, and non-AD dementias (combined n>3,400) who have been followed for 20-25 years and for whom we have detailed longitudinal cognitive, CSF, magnetic resonance imaging (MRI including ASL, FLAIR, and DTI), amyloid-positron emission tomography (amyloid-PET), and tau-PET imaging data. In Aim 1, we will examine the diagnostic and prognostic utility of CSF endothelial markers in AD and their ability to predict cognitive decline and brain atrophy over time, independently of amyloid and tau. We will also characterize baseline and longitudinal associations of endothelial dysfunction with CSF and/or imaging markers of amyloid, tau, inflammation, and neuronal/synaptic injury over 20-25 years of follow-up, including 10-15 years prior to symptom onset. In Aim 2, we will leverage event-based modeling (EBM; Aim 2A) in our cross-sectional cohorts and multifactorial data driven analyses (MFDDA; Aim 2B) in our longitudinal cohorts to propose new data-driven predictive models for AD which will elucidate the temporal ordering of fluid and imaging AD markers and the spatiotemporal progression of AD imaging markers (cerebral blood flow, amyloid and tau PET, and brain atrophy) across 37 brain regions and over 10-15 years prior to symptom onset. Functional pathway analyses of proteomic and RNA-seq data from our cohort and others will identify novel mechanisms by which endothelial dysfunction contributes to neurodegeneration, and influences synaptic plasticity, axonal repair, and abnormal protein aggregation in AD (Aim 2C). Through in-depth multi-omics analyses of endothelial dysfunction and the integration of multimodal data from large well-characterized longitudinal multiracial AD cohorts, we aim to propose a new disease model which will be the first to integrate endothelial dysfunction into the AD paradigm and will capture the molecular and pathological heterogeneity of AD beyond amyloid and tau. Findings from this study will provide novel insights into disease mechanisms and new molecular targets for AD drug discovery.