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

摘要 阿尔茨海默病(AD)是导致痴呆症的最常见原因之一，影响着500多万老年人 2020年的患者数量。在美国，受影响的患者数量可能会增长，到2040年将达到1000万， 这是对公共卫生保健的重大挑战。因此，当务之急是找到新的方法来提供 对阿尔茨海默病的发病和进展的机械论见解。虽然越来越多的证据表明 先天免疫系统在阿尔茨海默病中的关键作用，但研究相对较少的研究探讨了 获得性免疫细胞参与了AD的发病。 与遗传因素一样，环境因素也是导致神经退行性变的关键因素 精神障碍，包括阿尔茨海默病。肠道微生物，已被广泛研究，因为它们在塑造宿主 免疫功能，被认为是这些非遗传因素之一，定义了一个阈值 维持动态平衡或发展疾病。有趣的是，阿尔茨海默病患者经常表现出肠道生态失调， 提示肠道细菌的构成可能影响AD的发生发展。而当 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， 肠道细菌激活外周免疫细胞影响AD相关的潜在机制 表型尚不清楚。 在许多免疫细胞类型中，Th17细胞的独特位置是传递来自肠道的信号 细菌进入大脑。这些细胞是在肠道粘膜中诱导出来的，对共生细菌有反应，可以 迁移到脑膜中。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交流。 在……里面 在拟议的应用中，我们将评估肠道细菌-外周Th17三合一的贡献作用 细胞-大脑IL-17ra在促进AD相关病理和认知功能下降中的作用。我们将首先确定角色 IL-17a产生细胞在促进AD相关发病机制中的作用 在阿尔茨海默病的发展中促进Th17细胞生物发生的驻留细菌。第二，我们将揭开 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体研究，确定预防和 治疗措施，如益生菌或封闭抗体，以抑制患者的IL-17a反应 有发生AD相关认知功能减退的高风险。

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.