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

工程摘要 在≥90%的阿尔茨海默病（AD）患者脑中观察到脑内皮的结构和功能改变 在没有脑血管疾病或淀粉样血管病的情况下。尽管它的流行，内皮细胞的作用， AD发病机制中的功能障碍尚未得到充分研究，因为缺乏可靠的内皮细胞， 生物标志物。我们已经确定了一组新的内皮生物标志物，其脑核糖核酸（RNA）和 与对照相比，AD患者的脑脊液（CSF）蛋白水平显著改变。令人兴奋的初步 数据表明，这些蛋白质提供了作为脑内皮细胞的新的诊断和预后生物标志物的前景， 功能障碍，并与AD的认知和放射学结果密切相关。重要的是，我们的初步 AD模型提示内皮功能障碍是淀粉样变的早期病理基础 和tau。我们在这里建议进行第一次深入的全面翻译研究内皮细胞 AD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测量CSF蛋白和脑组织， 在3个大型的特征良好的迟发性散发性前列腺癌纵向队列中，这些内皮标志物的RNA水平 AD、健康对照和非AD痴呆（合并n> 3，400），随访20-25年， 我们对这些患者进行了详细的纵向认知、CSF、磁共振成像（MRI，包括ASL，FLAIR， 和DTI）、淀粉样蛋白-正电子发射断层扫描（淀粉样蛋白-PET）和tau-PET成像数据。在目标1中，我们 检查CSF内皮标志物在AD中的诊断和预后效用及其预测AD的能力。 随着时间的推移，认知能力下降和脑萎缩，与淀粉样蛋白和tau蛋白无关。我们还将描述 内皮功能障碍与CSF和/或淀粉样蛋白成像标志物的基线和纵向相关性， 在20-25年的随访中，包括在治疗前10-15年， 症状发作。在目标2中，我们将在横截面队列中利用基于事件的建模（EBM;目标2A） 和多因素数据驱动分析（MFDDA; Aim 2B），以提出新的数据驱动 AD的预测模型，其将阐明流体和成像AD标志物的时间顺序， AD成像标志物的时空进展（脑血流量、淀粉样蛋白和tau PET以及脑萎缩） 在37个脑区和症状发作前10-15年。蛋白质组功能途径分析 来自我们和其他人的RNA-seq数据将确定内皮功能障碍的新机制， 导致神经退行性变，并影响突触可塑性、轴突修复和异常蛋白 AD中的聚集（目的2C）。通过对内皮功能障碍的深入多组学分析， 整合来自大型多种族纵向AD队列的多模式数据，我们的目标是 提出了一种新的疾病模型，这将是第一个将内皮功能障碍整合到AD范式中的模型。 并且将捕获除了淀粉样蛋白和tau蛋白之外的AD的分子和病理异质性。时发现的问题 这项研究将为疾病机制和AD药物发现的新分子靶点提供新的见解。

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.