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.

项目摘要/摘要 阿尔茨海默氏病（AD）是一场国家健康危机，影响了许多年度总付款的美国人 预计到2050年预计将超过1万亿美元。阿尔茨海默氏病（AD）的风险是 遗传和环境风险因素随着年龄的增长，导致神经变性和 疾病发作。增加流行病学证据表明，受SARS-COV2感染的个体中约有80％， 以及发展covid-19，体验神经后遗症，其特征是 阿尔茨海默氏病，包括认知和神经精神缺陷。因此，有很大的可能性 基于生物学和宿主的SARS-COV2神经系统疾病的原因，例如阿尔茨海默氏病 对病毒的免疫反应。生物因子与中枢神经系统的过度活动交织在一起 COVID-19期间的炎症反应会影响中枢神经系统的功能状态。例如，双向 中枢神经系统注射与kynurenine（Kyn）途径（KP）的失调及其失调之间的关系 在血液和脑脊液中发现了代谢产物，例如雌二酸（Kyna）和喹啉酸（Quin）（Quin） AD患者的液体；和水平与相关的神经和认知障碍的严重程度相关 与艾滋病毒等病毒感染。重要的是，CoVID-19患者中KP代谢产物的破坏和失调 与疾病的严重程度相关，并由炎症诱导的吲哚胺2,3-二氧酶（IDO）触发。这 表明临界KP代谢物和SARS-COV2注射中枢神经系统的失调可能是 加剧AD发展的中枢神经系统的适应不良变化。因此，阐明 SARS-COV2诱导的KP失调与COVID-19和CNS注射之间的相互作用和 对AD疾病进展和神经病的影响。该提议的长期目标是 研究神经病发生的传染病危险因素和机制 SARS-COV2神经后遗症进展过程中的AD。使用鼠标适应的SARS-COV2，我们将 解决我们的整体目标：在SARS-COV2 CNS感染和进展过程中描述KP失调 阿尔茨海默氏症的神经病理学和神经认知下降与中枢神经系统免疫反应和 脑感染。中心假设是SARS-COV2是发作和 AD的严重程度，通过触发IDO活动，从而使外围和中枢神经系统中的KP代谢产物失调 加剧随后的细胞因子风暴，以加剧AD神经病理学。为了解决这一假设，我们 会1）区分SARS-COV2感染后与广告相关的认知下降加剧，2）划定SARS- COV2神经病理学，疾病伯恩和AD中宿主免疫学和KP信号的双重激活，3） 在SARS-COV2介导的AD发作和严重程度加重中阐明了特定的IDO贡献。这 提案将提供一种以免疫KP为中心的方法来识别SARS-COV2对 AD中的神经退行性过程。