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.

抽象的 阿尔茨海默病 (AD) 是导致痴呆症的最常见原因之一，影响超过 500 万老年人 到 2020 年，美国受影响的患者人数可能会增加，到 2040 年将达到 1000 万， 这对公共卫生保健构成了重大挑战，因此必须找到提供新方法的方法。 越来越多的证据表明，AD 的发病和进展的机制。 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。 除了遗传因素外，环境因素也是导致神经退行性疾病的关键因素 疾病，包括肠道微生物，它们在塑造宿主的过程中的作用已被广泛研究。 免疫功能，被认为是这些非遗传因素之一，定义了任一阈值 有趣的是，AD 患者经常表现出肠道菌群失调， 表明肠道细菌的组成可能会影响 AD 的发生和进展。 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 相关的潜在机制 表型未知。 在众多免疫细胞类型中，Th17 细胞具有独特的地位，可以传递来自肠道的信号 这些细胞是在肠道粘膜中对共生细菌做出反应而被诱导的。 我们和其他人还表明，IL-17a 的受体（即 IL-17Ra）是 在成人大脑中表达，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三联体——外周 Th17 的贡献作用 细胞-脑IL-17Ra在促进AD相关病理和认知能力下降中的作用我们首先确定。 IL-17a 产生细胞在促进 AD 相关发病机制中的作用，并确定肠道的贡献作用 其次，我们将揭示在 AD 发展过程中增强 Th17 细胞生物发生的细菌。 IL-17a 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确定预防和预防措施 治疗措施，例如益生菌或阻断抗体，以抑制患者的 IL-17a 反应 发生 AD 相关认知能力下降的风险很高。