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.

项目概要/摘要 阿尔茨海默病 (AD) 是一场全国性的健康危机，影响着许多美国人的年付款总额 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： 随着年龄的增长，遗传和环境风险因素会驱动病理学，导致神经退行性变和 疾病发作。越来越多的流行病学证据表明，约 80% 的 SARS-CoV2 感染者， 患有 Covid-19 的人会出现神经系统后遗症，其常见病因如下： 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 基于生物学和宿主的 SARS-CoV2 导致神经系统疾病（例如阿尔茨海默病）的原因 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 期间的炎症反应会影响中枢神经系统的功能状态。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 患有病毒感染，例如艾滋病毒。重要的是，Covid-19 患者 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-CoV2 对关键 KP 代谢物和中枢神经系统炎症的失调可能是其原因 中枢神经系统的适应不良变化加剧了 AD 的发展。因此，阐明这一点至关重要 Covid-19 期间 SARS-CoV2 诱导的 KP 失调与中枢神经系统炎症之间的相互作用 对 AD 疾病进展和神经发病机制的影响。该提案的长期目标是 研究传染病的危险因素和神经发病机制 AD 在 SARS-CoV2 神经系统后遗症进展过程中的作用。使用小鼠适应的 SARS-CoV2，我们将 解决我们的总体目标：描述 SARS-CoV2 CNS 感染和进展期间 KP 失调 阿尔茨海默病的神经病理学和与中枢神经系统免疫反应相关的神经认知能力下降 脑炎感染。中心假设是 SARS-CoV2 是该病发病和传播的一个重要危险因素。 AD 的严重程度，通过触发 IDO 活性从而失调外周和 CNS 中的 KP 代谢物， 加剧随后的细胞因子风暴，从而加剧 AD 神经病理学。为了解决这个假设，我们 将 1) 区分 SARS-CoV2 感染后加剧的 AD 相关认知能力下降，2) 描述 SARS- AD 中的 CoV2 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-CoV2 介导的 AD 发病和严重程度恶化中的具体作用。这 该提案将提供一种以免疫 KP 为重点的方法来识别 SARS-CoV2 对 AD 中的神经退行性过程。