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

阿尔茨海默病和 SARS-CoV-2 感染的相关痴呆样后遗症：病毒-宿主相互作用组、神经病理生物学和药物再利用

• 批准号: 10661931
• 负责人: Feixiong Cheng
• 金额: $ 239.45万
• 依托单位: CLEVELAND CLINIC LERNER COM-CWRU
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-05-15 至 2026-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10661931
• 关键词: 2019-nCoV; AD transgenic mice; Abeta synthesis; Accounting; Address; Affect; Age; Alzheimer' s Disease; Alzheimer' s disease patient; Alzheimer' s disease related dementia; Alzheimer' s disease risk; American; Automobile Driving; Biological Markers; Brain; COVID-19; COVID-19 pandemic effects; COVID-19 patient; COVID-19 severity; Cell Death; Cell Line; Cell Nucleus; Clinic; Clinical Trials; Complex; Data; Data Analyses; Databases; Dementia; Development; Disease; Disease Outcome; Drug Targeting; Electronic Health Record; Endothelium; Etiology; FDA approved; Female; Functional disorder; Gene Expression Profile; Genetic Transcription; Genomics; Goals; Heterogeneity; Human; Induced pluripotent stem cell derived neurons; Injury; Integration Host Factors; Lead; Link; Long COVID; Maps; Medicine; Melatonin; Methodology; Molecular; Morphology; Network-based; Neurocognitive; Neurocognitive Deficit; Neurodegenerative Disorders; Neuroimmune; Neurons; Open Reading Frames; Pathologic; Pathway interactions; Patients; Persons; Pharmaceutical Preparations; Pharmacoepidemiology; Pharmacotherapy; Phenotype; Population; Prevention; Process; Property; Proteins; Publications; Research; Risk; SARS-CoV-2 infection; Synapses; Systems Biology; Techniques; Technology; Testing; Therapeutic; Tissue Donors; Transgenic Mice; United States; Validation; Viral; Virus; Virus Diseases; brain cell; brain endothelial cell; brain tissue; cell type; coronavirus disease; drug repurposing; drug testing; effective therapy; efficacy evaluation; epigenomics; gene network; human coronavirus; human interactome; induced pluripotent stem cell; insight; male; mild cognitive impairment; mouse model; multimodality; neuroinflammation; neurologic sequelae of COVID-19; new therapeutic target; novel; overexpression; pathogen; patient registry; population based; risk variant; sex; single nucleus RNA-sequencing; stem cell model; targeted treatment; tau aggregation; tau-1; therapeutic development; valacyclovir; vascular injury

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

项目概要 大量跨学科证据表明，存在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 我们正在研究病原体（尤其是病毒）的神经炎症和微血管损伤。 与 2019 年人类冠状病毒病 (COVID-19) 有关的 AD/ADRD 的研究，该疾病是由严重急性呼吸道疾病引起的 值得注意的是，仅在美国就有超过 8700 万例呼吸综合征冠状病毒 2 (SARS-CoV-2)。 大量证据表明 COVID-19 会产生神经认知后遗症，这最终可能导致 AD/ADRD 和其他形式的神经认知障碍病例激增。我们团队的初步证据。 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 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图谱可以识别新的病理生理途径和药物靶标以保护 因此，我们假设对 SARS-CoV-2 人类的大脑进行多模式分析。 患者诱导多能干细胞 (iPSC) 来源的脑微血管内皮细胞的相互作用组图谱 来自 de novo AD/ADRD 样神经认知的细胞 (BMEC) 和大脑单核基因组/表观基因组数据 COVID-19 患者（Neurcogn-COVID）的损伤将为复杂的情况提供有价值的、公正的见解 该项目将在分子、细胞和网络水平上研究 SARS-CoV-2 的神经认知后遗症的病因学。 阐明对脑细胞类型特异性病毒-人类蛋白质相互作用组抑制靶标的批判性理解 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图谱 使用我们的高通量识别 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。目标 1 将询问 SARS-CoV-2 病毒-人类相互作用组以识别和 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 系）。目标 2 将询问细胞类型特异性神经免疫和脑内皮转录。 网络来识别与病毒引起的神经炎症和脑微血管损伤相关的病理生理学。 我们将利用从遭受苦难的捐赠者的脑组织中生成的单核基因组/表观基因组数据 来自神经认知-COVID、AD、轻度认知障碍 (MCI) 以及年龄、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 的 Aim 3 将测试该功能。 假设可以确定药物在神经认知后遗症中重新利用的潜在新机会 通过将基于群体的纵向验证和小鼠模型的功能测试相结合。 该项目的成功完成将阐明 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，以便在临床试验中直接进行测试。 1