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

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.

摘要 阿尔茨海默病（AD）是痴呆症的最常见原因之一，影响超过500万老年人 2020年患者受影响的患者人数可能会在美国增长，到2040年将达到1000万， 这对公共卫生保健构成了重大挑战。因此，必须找到新的方法， 对AD的发病和进展的机制性见解。虽然越来越多的证据表明， 先天免疫系统在AD中的关键功能，相对较少的研究调查了其机制， 适应性免疫细胞有助于AD的发病机制。 沿着遗传因素，环境因素是驱动神经退行性变的关键因素。 疾病，包括AD。肠道微生物，已被广泛研究其在塑造宿主的 免疫功能，被认为是这些非遗传因素之一，定义了一个阈值， 维持体内平衡或发展疾病。有趣的是，AD患者经常表现出肠道生态失调， 这表明肠道驻留细菌的组成可能影响AD的发生和进展。而 近年来的许多研究表明，肠道细菌和免疫细胞会影响大脑功能， 肠道细菌赋予外周免疫细胞影响AD相关疾病的潜在机制 表型未知。 在众多免疫细胞类型中，Th 17细胞具有独特的地位，可以传递来自肠道驻留细胞的信号 细菌进入大脑。这些细胞在肠道粘膜中响应于肠道细菌而被诱导， 迁移到脑膜中我们和其他人还表明，IL-17 α的受体，即IL-17 Ra， 在成人大脑中表达，并促进免疫系统和神经系统之间的沟通。 在 在拟议的应用中，我们将评估肠道细菌-外周Th 17三联体的作用 细胞脑IL-17 Ra促进AD相关的病理和认知能力下降。我们将首先确定角色 IL-17 a产生细胞在促进AD相关发病机制中的作用，并确定肠- 在AD的发展中增强Th 17细胞生物发生的驻留细菌。第二，我们将揭开 IL-17 a在AD发展过程中影响脑细胞的潜在机制。 这项研究的成功完成可能会导致未来的人类研究， 治疗措施，如益生菌或封闭抗体，以抑制患者的IL-17 a反应 患上AD相关认知能力下降的风险很高。