Alzheimer's Disease and Related Dementia-like Sequelae of SARS-CoV-2 Infection: Virus-Host Interactome, Neuropathobiology, and Drug Repurposing

项目摘要 大量的跨学科证据表明，有多种病理生理过程驱动 阿尔茨海默病（AD）和AD相关痴呆（ADRD）的发生和进展，包括 神经炎症和微血管损伤的病原体，特别是病毒。我们正在研究这些方面 AD/ADRD与2019年人类冠状病毒病（COVID-19）有关，这是由严重急性 呼吸道综合征冠状病毒2（SARS-CoV-2），仅在美国就有超过8700万例病例。值得注意的是， 大量证据表明COVID-19的神经认知后遗症，最终可能导致 AD/ADRD和其他形式的神经认知障碍病例激增。我们小组的初步证据显示 确定SARS-CoV-2感染引起神经炎症和脑微血管损伤，这两个主要的 AD/ADRD的危险因素。我们还证明了人类和病毒的系统特征， 人类蛋白质相互作用组图谱可以识别新的病理生理途径和药物靶点， 感染了SARS-CoV-2的大脑因此，我们认为SARS-CoV-2-人的多模式分析 患者诱导的多能干细胞（iPSC）衍生的脑微血管内皮细胞中的相互作用组图谱 细胞（BMEC）和来自从头AD/ADRD样神经认知的脑单核基因组/表观基因组数据 在COVID-19患者的损伤（Neurocogn-COVID），将提供有价值的公正的见解复杂 SARS-CoV-2神经认知后遗症的分子、细胞和网络水平的病因学。该项目将 阐明对脑细胞类型特异性病毒-人蛋白质相互作用组抑制靶点的重要理解 以及病毒感染后可能导致AD/ADRD的神经免疫基因网络和脑微血管损伤。 我们的近期目标是建立一个全面的、脑细胞类型特异性的病毒-人类蛋白质相互作用组图谱 用于使用我们的高通量技术鉴定SARS-CoV-2感染的神经认知后遗症的分子驱动因素， 蛋白质相互作用组学平台目的1将询问SARS-CoV-2病毒-人相互作用组以鉴定和 验证iPSC衍生的BMEC中ADRD样病毒微血管损伤的分子驱动因素（年龄，性别，APOE， 匹配的iPSC线）。目标2将询问细胞类型特异性神经免疫和脑内皮转录 网络，以确定与病毒诱导的神经炎症和脑微血管损伤相关的病理生理学。 我们将利用单核基因组/表观基因组数据，这些数据是从患有脑损伤的捐赠者的脑组织中产生的。 来自神经认知-COVID、AD、轻度认知障碍（MCI）和年龄、性别、APOE匹配的健康对照 来自克利夫兰阿尔茨海默病研究中心（ADRC）和西北ADRC。目标3将测试 假设可以确定神经认知后遗症中药物再利用的潜在新机会 通过结合纵向基于群体的验证和小鼠模型中的功能测试。 成功完成该项目将阐明SARS神经认知后遗症的机制生物标志物- CoV-2，并确定新的药物靶点和治疗方法，以直接在临床试验中进行测试。 1

PROJECT SUMMARY Abundant cross-interdisciplinary evidence indicates that there are multiple pathophysiological processes driving development and progression of Alzheimer’s disease (AD) and AD-related dementias (ADRD), including neuroinflammation and microvascular injury to pathogens, especially viruses. We are examining these aspects of AD/ADRD with respect to human coronavirus disease 2019 (COVID-19), which is caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) with over 87 million cases in the United States alone. Notably, substantial evidence indicates neurocognitive sequelae of COVID-19, which are poised to ultimately lead to a surge in cases of AD/ADRD, and other forms of neurocognitive impairment. Preliminary evidence from our team identified that SARS-CoV-2 infection caused neuroinflammation and brain microvascular injury, two major risk factors for AD/ADRD. We have also demonstrated that systematic characterization of human- and virus- human protein interactome maps can identify novel pathophysiological pathways and drug targets to protect the SARS-CoV-2-infected brains. We therefore posit that multimodal analyses of SARS-CoV-2-human interactome maps in patient induced pluripotent stem cell (iPSC)-derived brain microvascular endothelial cells (BMECs) and brain single-nucleus genomic/epigenomic data from de novo AD/ADRD-like neurocognitive impairment in COVID-19 patients (Neurocogn-COVID), will provide valuable unbiased insights into the complex etiology of neurocognitive sequelae of SARS-CoV-2 at molecular, cellular and network levels. This project will elucidate critical understanding of both brain cell type-specific virus-human protein interactome-inhibitory targets and neuro-immune gene networks and brain microvascular injury that may lead to AD/ADRD after viral infection. Our immediate goal is to build a comprehensive, brain cell type-specific virus-human protein interactome map for identifying molecular drivers for neurocognitive sequelae of SARS-CoV-2 infection using our high-throughput protein interactomics platform. Aim 1 will interrogate the SARS-CoV-2 virus-human interactome to identify and validate molecular drivers of ADRD-like viral microvascular injury in iPSC-derived BMECs (age-, sex-, APOE- matched iPSC lines). Aim 2 will interrogate cell type-specific neuroimmune and brain endothelial transcriptional networks to identify pathophysiology related to virus-induced neuro-inflammation and brain microvascular injury. We will leverage single-nucleus genomic/epigenomic data generated from brain tissues of donors who suffered from neurocogn-COVID, AD, mild cognitive impairment (MCI), and age-, sex-, APOE-matched healthy controls from the Cleveland Alzheimer's Disease Research Center (ADRC) and Northwestern ADRC. Aim 3 will test the hypothesis that potential new opportunities for drug repurposing in neurocognitive sequelae can be identified through a combination of longitudinal population-based validation and functional testing in mouse models. Successful completion of this project will elucidate mechanistic biomarker for neurocognitive sequelae of SARS- CoV-2 and identify new drug targets and treatments to be directly tested in clinical trials. 1