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

项目总结 大量的跨学科交叉证据表明，有多种病理生理过程推动 阿尔茨海默病(AD)和AD相关痴呆(ADRD)的发展和进展，包括 对病原体，尤其是病毒的神经炎症和微血管损伤。我们正在研究这些方面 关于2019年人类冠状病毒病的AD/ADRD(新冠肺炎)，这是由严重急性冠状病毒引起的 仅在美国就有8700多万人感染了呼吸综合征冠状病毒2(SARS-CoV-2)。值得注意的是， 大量证据表明，新冠肺炎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。来自我们团队的初步证据 确认SARS-CoV-2感染引起的神经炎症和脑微血管损伤两大类 AD/ADRD的危险因素。我们还证明了对人类和病毒的系统描述 人类蛋白质相互作用组图可以识别新的病理生理途径和保护的药物靶点 感染SARS-CoV-2的大脑。因此，我们假设SARS-CoV-2-人类的多模式分析 患者诱导的多能干细胞来源的脑微血管内皮细胞的相互作用组图 来自新AD/ADRD样神经认知的细胞(BMECs)和脑单核基因组/表观基因组数据 新冠肺炎患者的损害(神经外科-COVID)，将为了解该复合体提供有价值的、公正的见解 从分子、细胞和网络水平探讨SARS-CoV-2神经认知后遗症的病因。这个项目将 阐明对脑细胞类型特异性病毒-人蛋白相互作用抑制靶点的关键理解 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、脑细胞类型特定的病毒-人类蛋白质相互作用组图。 使用我们的高通量技术确定SARS-CoV-2感染的神经认知后遗症的分子驱动因素 蛋白质互作平台。AIM 1将询问SARS-CoV-2病毒与人类的相互作用组，以识别和 验证IPSC来源的BMECs中ADRD样病毒微血管损伤的分子驱动因素(年龄、性别、载脂蛋白- 匹配的IPSC线路)。AIM 2将询问特定细胞类型的神经免疫和脑内皮细胞转录 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。 我们将利用从患者脑组织中产生的单核基因组/表观基因组数据 来自Neurocon-COVID、AD、轻度认知障碍(MCI)和年龄、性别、APOE匹配的健康对照组 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 可以确定神经认知后遗症中潜在的药物再利用的新机会的假设 通过在小鼠模型中进行纵向基于总体的验证和功能测试相结合。 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-- 并确定新的药物靶点和治疗方法，以便在临床试验中直接测试。 1