Targeting IDO in SARS-CoV2-induced Alzheimer's Disease progression

在 SARS-CoV2 诱导的阿尔茨海默病进展中靶向 IDO

• 批准号: 10670498
• 负责人: Irma Cisneros
• 金额: $ 40万
• 依托单位: UNIVERSITY OF TEXAS MED BR GALVESTON
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10670498
• 关键词: 2019-nCoV; Address; Advanced Development; Affect; Age; Alzheimer' s Disease; Alzheimer' s disease patient; Alzheimer' s disease risk; Alzheimer' s neuropathogenesis; American; Amyloid beta-Protein; Animal Disease Models; Area; Automobile Driving; Behavioral; Biological Factors; Biological Markers; Biology; Blood; Brain; COVID-19; COVID-19 impact; COVID-19 patient; Cause of Death; Cells; Central Nervous System Infections; Cerebrospinal Fluid; Characteristics; Cognitive; Communicable Diseases; Confusion; Data; Delirium; Deposition; Development; Disease Progression; Encephalitis; Environmental Risk Factor; Enzymes; Epidemiology; Etiology; Future; Goals; HIV; Health; Histologic; Hospitalization; Human; Immune; Immune response; Immunity; Immunologic Markers; Impaired cognition; Individual; Infection; Infiltration; Inflammation; Inflammatory; Inflammatory Response; Ingestion; Inherited; Kynurenic Acid; Kynurenine; Learning; Link; Lymphocyte; Measures; Mediating; Memory; Memory impairment; Metabolic; Mus; Nerve Degeneration; Neuraxis; Neurocognitive Deficit; Neurodegenerative Disorders; Neurologic; Neuropathogenesis; Onset of illness; Pathology; Pathway interactions; Patients; Peripheral; Physiological; Process; Production; Public Health; Quinolinic Acid; Research; Risk; Risk Factors; Route; SARS-CoV-2 infection; SARS-CoV-2 inhibitor; Severities; Severity of illness; Signal Pathway; Signal Transduction; Testing; Tg2576; Transgenic Organisms; Tryptophan; Tryptophan 2,3 Dioxygenase; United States; Virus; Virus Diseases; Wild Type Mouse; base; burden of illness; cognitive process; cytokine release syndrome; dysphoria; experience; functional status; global health; insight; neurobehavior; neuroinflammation; neurologic sequelae of COVID-19; neuropathology; neuropsychiatry; pathogen; payment; post SARS-CoV-2 infection; pre-clinical; response; tau Proteins; therapeutic development; translational study

Project Summary/Abstract Alzheimer’s disease (AD) is a national health crisis, affecting many Americans with total annual payments projected to be more than $1 trillion by 2050. The risk for Alzheimer’s disease (AD) is an interaction between inherited and environmental risk factors that, with age, drives pathology resulting in neurodegeneration and disease onset. Increasing epidemiological evidence indicates that ~80% of individuals infected with SARS-CoV2, and who develop Covid-19, experience neurological sequelae characterized by common etiological factors of Alzheimer’s disease, including cognitive and neuropsychiatric deficits. Therefore, there is a strong possibility in SARS-CoV2 causation of neurological conditions, such as Alzheimer’s disease, based on the biology and host immune responses to the virus. Biological factors intertwined with the overactivity of the CNS inflammatory response during Covid-19, impact the functional status of the CNS. For example, the bidirectional relationship between CNS inflammation and dysregulation of the kynurenine (KYN) pathway (KP) and its metabolites, such as kynurenic acid (KYNA) and quinolinic acid (QUIN), are found in the blood and cerebrospinal fluid of AD patients; and levels are correlated to severity of neurological and cognitive impairments associated with viral infections such as HIV. Importantly, disruption and dysregulation of KP metabolites in Covid-19 patients is correlated to disease severity and triggered by inflammation-induced indoleamine 2,3-dioxygenase (IDO). This indicates that dysregulation of critical KP metabolites and CNS inflammation by SARs-CoV2 may underlie maladaptive changes in the CNS that exacerbate the development of AD. Therefore, it is critical to elucidate the interplay between SARS-CoV2-induced KP dysregulation and CNS inflammation during Covid-19 and the impact on AD disease progression and neuropathogenesis. The long-term goal of this proposal is to investigate the infectious disease risk factors and mechanisms underlying the neuropathogenesis of AD during the progression of SARS-CoV2 neurological sequelae. Using mouse-adapted SARS-CoV2, we will address our overall objective: to delineate KP dysregulation during SARS-CoV2 CNS infection and progression of Alzheimer’s neuropathology and neurocognitive decline correlative to CNS immune responses and encephalitic infection. The central hypothesis is that SARS-CoV2 is a significant risk factor for the onset and severity of AD, by triggering IDO activity thereby dysregulating KP metabolites in the periphery and CNS and exacerbating the subsequent cytokine storm to exacerbate AD neuropathology. To address this hypothesis, we will 1) distinguish AD-related cognitive decline exacerbated following SARS-CoV2 infection, 2) delineate SARS- CoV2 neuropathology, disease burden, and dual activation of host immunity and KP signaling in AD, and 3) elucidate specific IDO contributions in SARs-CoV2-mediated exacerbation of AD onset and severity. This proposal will provide an immune-KP focused approach to identify SARS-CoV2 on the impact of neurodegenerative processes in AD.

项目总结/摘要 阿尔茨海默病（AD）是一个全国性的健康危机，影响到许多美国人与总年度支付 预计到2050年将超过1万亿美元。阿尔茨海默病（AD）的风险是以下因素之间的相互作用： 遗传和环境风险因素，随着年龄的增长，驱动病理导致神经退行性变， 发病越来越多的流行病学证据表明，约80%的SARS-CoV 2感染者， 和谁开发新冠肺炎，经历神经系统后遗症的特点是常见的病因因素， 阿尔茨海默病，包括认知和神经精神缺陷。因此，有很大的可能性， SARS-CoV 2导致神经系统疾病，如阿尔茨海默病，基于生物学和宿主 对病毒的免疫反应。生物因素与中枢神经系统过度活跃交织在一起 COVID-19期间的炎症反应，影响CNS的功能状态。例如，双向 中枢神经系统炎症与犬尿氨酸（KYN）通路（KP）失调之间的关系及其 代谢物，如犬尿烯酸（KYNA）和喹啉酸（QUIN），存在于血液和脑脊液中， AD患者的体液;并且水平与神经和认知障碍的严重程度相关， 病毒感染，如艾滋病。重要的是，在Covid-19患者中KP代谢物的破坏和失调 与疾病严重程度相关，并由炎症诱导的吲哚胺2，3-双加氧酶（IDO）触发。这 表明SARS-CoV 2引起的关键KP代谢物和CNS炎症的失调可能是 中枢神经系统的适应不良变化加剧了AD的发展。因此，阐明 在Covid-19期间SARS-CoV 2诱导的KP失调和CNS炎症之间的相互作用以及 影响AD疾病进展和神经发病机制。该提案的长期目标是 研究感染性疾病的危险因素和神经发病机制 在SARS-CoV 2神经系统后遗症的进展过程中AD。使用小鼠适应的SARS-CoV 2，我们将 阐明我们的总体目标：描述SARS-CoV 2 CNS感染和进展过程中KP的失调 阿尔茨海默病的神经病理学和神经认知功能下降与中枢神经系统免疫反应， 脑炎感染中心假设是SARS-CoV 2是发病的重要危险因素， AD的严重程度，通过触发IDO活性，从而使外周和CNS中的KP代谢物失调， 加剧随后的细胞因子风暴以加剧AD神经病理学。为了解决这个问题，我们 将1）区分SARS-CoV 2感染后AD相关的认知功能下降，2）描述SARS- AD中CoV 2神经病理学、疾病负担以及宿主免疫和KP信号传导的双重激活，以及3） 阐明IDO在SARS-CoV 2介导的AD发作和严重程度加重中的具体作用。这 建议将提供一个免疫KP为重点的方法，以确定SARS-CoV 2对 AD中的神经退行性过程。