Dissecting the modulatory functions of interleukin-17 in Alzheimer's Disease

剖析 IL-17 在阿尔茨海默病中的调节功能

• 批准号: 10590495
• 负责人: Jun R. Huh
• 金额: $ 235.96万
• 依托单位: HARVARD MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-12-15 至 2025-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10590495
• 关键词: Address; Adult; Affect; Alzheimer' s Disease; Alzheimer' s disease pathology; Alzheimer' s disease patient; Animal Model; Automobile Driving; Bacteria; Biogenesis; Blocking Antibodies; Blood Circulation; Brain; Brain Pathology; CD4 Positive T Lymphocytes; Cell physiology; Cells; Cellular immunotherapy; Code; Communication; Dementia; Development; Disease; Disease Progression; Environmental Risk Factor; Future; Genetic; Goals; Gut Mucosa; Healthcare; Homeostasis; Human; IL17 gene; Immune; Immune response; Immune system; Impaired cognition; Individual; Innate Immune System; Interleukin Receptor; Interleukins; Longitudinal Studies; Measures; Meninges; Mus; Nervous System; Neurodegenerative Disorders; Neurons; Onset of illness; Pathogenesis; Pathogenicity; Pathology; Patients; Pattern; Peripheral; Phenotype; Play; Positioning Attribute; Predisposition; Preventive; Probiotics; Process; Production; Public Health; Research; Role; Shapes; Signal Transduction; Spatial Distribution; Symptoms; Testing; Therapeutic; Therapeutic antibodies; Translating; United States; Work; adaptive immune response; age related; aged; brain cell; cell type; commensal bacteria; cytokine; design; disease phenotype; empowerment; gastrointestinal symptom; gut bacteria; gut dysbiosis; gut microbes; gut microbiota; high risk; high risk population; immune function; innate immune function; insight; interleukin-23; migration; mouse model; neuromechanism; non-genetic; novel; older patient; pre-clinical; receptor; receptor expression; response; Address; Adult; Affect; Alzheimer' s Disease; Alzheimer' s disease pathology; Alzheimer' s disease patient; Animal Model; Automobile Driving; Bacteria; Biogenesis; Blocking Antibodies; Blood Circulation; Brain; Brain Pathology; CD4 Positive T Lymphocytes; Cell physiology; Cells; Cellular immunotherapy; Code; Communication; Dementia; Development; Disease; Disease Progression; Environmental Risk Factor; Future; Genetic; Goals; Gut Mucosa; Healthcare; Homeostasis; Human; IL17 gene; Immune; Immune response; Immune system; Impaired cognition; Individual; Innate Immune System; Interleukin Receptor; Interleukins; Longitudinal Studies; Measures; Meninges; Mus; Nervous System; Neurodegenerative Disorders; Neurons; Onset of illness; Pathogenesis; Pathogenicity; Pathology; Patients; Pattern; Peripheral; Phenotype; Play; Positioning Attribute; Predisposition; Preventive; Probiotics; Process; Production; Public Health; Research; Role; Shapes; Signal Transduction; Spatial Distribution; Symptoms; Testing; Therapeutic; Therapeutic antibodies; Translating; United States; Work; adaptive immune response; age related; aged; brain cell; cell type; commensal bacteria; cytokine; design; disease phenotype; empowerment; gastrointestinal symptom; gut bacteria; gut dysbiosis; gut microbes; gut microbiota; high risk; high risk population; immune function; innate immune function; insight; interleukin-23; migration; mouse model; neuromechanism; non-genetic; novel; older patient; pre-clinical; receptor; receptor expression; response

ABSTRACT Alzheimer’s Disease (AD) is one of the most common causes of dementia, affecting over 5 million elderly patients in 2020. The affected patient number will likely grow in the United States and reach 10 million by 2040, representing a significant challenge to public health care. It is thus imperative to find novel ways that offer mechanistic insights into the onset and the progression of AD. While a growing body of evidence indicates the critical function of innate immune systems in AD, relatively few studies investigated mechanisms by which adaptive immune cells contribute to the pathogenesis of AD. Along with genetic factors, environmental factors are critical contributors to driving neurodegenerative disorders, including AD. Gut microbes, which have been extensively studied for their roles in shaping the host’s immune function, are being recognized as one of these non-genetic factors that define a threshold to either maintaining homeostasis or developing diseases. Intriguingly, AD patients often display gut dysbiosis, suggesting that the make-up of gut-residing bacteria may affect the development and progression of AD. While many studies in recent years have shown that gut-residing bacteria and immune cells affect brain function, the underlying mechanisms by which gut bacteria empower peripheral immune cells to influence AD-related phenotypes are unknown. Among the many immune cell types, Th17 cells are uniquely positioned to relay signals from gut-residing bacteria to the brain. These cells are induced in the gut mucosa in response to a commensal bacterium and can migrate into the meninges. We and others have also shown that a receptor for IL-17a, namely IL-17Ra, is expressed in the adult brain and facilitates the communication between the immune and nervous systems. In the proposed application, we will assess the contributing roles of the triad of gut bacteria-peripheral Th17 cells-brain IL-17Ra in promoting AD-related pathologies and cognitive decline. We will first identify the role of IL-17a-producing cells in promoting AD-related pathogenesis and determine the contributing roles of gut- residing bacteria that enhance Th17 cell biogenesis in the development of AD. Second, we will uncover the underlying mechanisms by which IL-17a affects brain cells during AD development. Successful completion of this study will likely lead to future human studies identifying preventive and therapeutic measures, such as probiotics or blocking antibodies, to suppress the IL-17a responses in patients with a high risk of developing AD-related cognitive decline.

抽象的 阿尔茨海默氏病（AD）是痴呆症最常见的原因之一，较早影响超过500万 2020年的患者。受影响的患者人数在美国可能会增加，到2040年达到1000万 代表了对公共卫生保健的重大挑战。因此，必须找到提供的新方法 对AD的发作和进展的机械洞察力。越来越多的证据表明 先天免疫系统在AD中的关键功能，相对较少的研究研究了机制 自适应免疫细胞有助于AD的发病机理。 与遗传因素一起，环境因素是驱动神经退行性的关键因素 疾病，包括广告。肠道微生物，这些微生物在塑造主机方面的角色已广泛研究 免疫功能被认为是这些非遗传因素之一，这些因素定义了一个阈值 维持体内稳态或发展疾病。有趣的是，AD患者经常表现出肠道营养不良， 表明肠道遗化细菌的构成可能会影响AD的发展和发展。尽管 近年来，许多研究表明，肠道遗化细菌和免疫细胞会影响大脑功能， 肠道细菌赋予周围免疫力影响AD相关的基本机制 表型未知。 在许多免疫细胞类型中，Th17细胞可独特地定位于肠道远程信号 大脑的细菌。这些细胞在响应共生细菌的肠道粘膜中诱导，可以 迁移到脑膜上。我们和其他人还表明，IL-17A的接收器，即IL-17RA，是 在成人大脑中表达，并促进免疫系统和神经系统之间的通信。 在 拟议的应用，我们将评估肠道细菌 - 外围Th17的三合会的作用 细胞脑IL-17RA在促进广告相关的病理和认知下降方面。我们将首先确定角色 产生IL-17A的细胞在促进广告相关的发病机理中的产生，并确定肠道的作用 在AD发育中占据了增强Th17细胞生物发生的细菌。第二，我们将发现 IL-17A在AD发育过程中影响脑细胞的基本机制。 成功完成这项研究可能会导致未来的人类研究确定预防性和 治疗措施，例如益生菌或阻断抗体，以抑制患者的IL-17A反应 有高风险患广告相关的认知能力下降。