Gut Immunity, Neurovascular dysregulation and Cognitive Impairment

阿尔茨海默病及相关痴呆（ADRDs）是一组与年龄相关的疾病 影响认知功能，对此没有可用的治疗。神经炎症和 神经血管功能障碍已成为ADRD疾病进展的关键驱动因素。在 特别是，脑内皮细胞和小胶质细胞，脑固有的先天免疫细胞，已经被 与过度磷酸化的tau蛋白（一种微管相关蛋白）的积累有关， ADRD病理学的一个关键特征。外周免疫系统失调也可能 发挥作用，并可能影响内皮和小胶质细胞功能，有助于认知 损伤然而，外周免疫系统如何与大脑沟通， 微血管系统和小胶质细胞改变认知功能的作用仍有待充分建立。 产生IL 17的辅助性T淋巴细胞（Th 17细胞），辅助性T淋巴细胞的一个亚群，和 它们的标志性细胞因子IL 17与认知损害的机制有关。 先前的数据表明，循环Th 17衍生的IL 17作用于脑内皮细胞， 诱导内皮一氧化氮（NO）缺陷，促进tau积累和认知 损伤由于它们在肠道中的丰度，Th 17细胞对肠道细菌特别敏感 并且肠道植物群的改变与Th 17细胞的失调有关。分段 丝状菌（SFB）是一种能有效诱导小鼠肠道Th 17细胞的肠道细菌 并改变Th 17细胞相关疾病模型的进程。因此，肠道Th 17 SFB诱导的神经功能失调可作为研究神经功能失调的模型， 了解肠道Th 17细胞如何改变大脑健康在这些基础上，我们建议测试 中心假设，肠道Th 17细胞的失调，诱导的殖民小 肠与SFB，促进IL 17介导的脑内皮细胞炎症反应 这些细胞反过来激活小胶质细胞，导致tau蛋白积累和认知障碍。到 为此，目前的拨款申请将检查内皮功能，tau病理学和 在SFB定殖的小鼠模型中的认知功能，以测试以下在雄性中的假设， 雌性和老龄小鼠：（1）肠道SFB定植促进肠道Th 17分化， 循环IL 17并诱导脑血管和认知障碍;（2）循环IL 17 通过激活大脑介导脑血管功能障碍和认知障碍 内皮IL 17受体;（3）IL 17诱导的内皮促炎介质激活 小胶质细胞导致tau积累和认知障碍。拟议的研究填补了 在理解肠道微生物群对认知的影响以及 循环IL 17、内皮细胞和小胶质细胞介导这些作用。而且这些 这些发现可能揭示了微生物群诱导的肠道Th 17细胞失调之间的新联系， 脑tau蛋白积聚和认知障碍，具有潜在的公共卫生影响。

Alzheimer’s disease and related dementias (ADRDs) are a group of age-related diseases affecting cognitive function for which no treatments are available. Neuroinflammation and neurovascular dysfunction have emerged as crucial drivers of disease progression in ADRDs. In particular, cerebral endothelial cells and microglia, brain resident innate-immune cells, have been implicated in the accumulation of hyperphosphorylated tau, a microtubule associated protein and a key feature of ADRD’s pathology. Dysregulation of the peripheral immune system could also play a role and may influence endothelial and microglial function contributing to cognitive impairment. However, how the peripheral immune system communicates with the cerebral microvasculature and microglia to alter cognitive function remains to be fully established. IL17-producing T-helper lymphocytes (Th17 cells), a subset of T-helper lymphocytes, and their signature cytokine, IL17, have been implicated in the mechanisms of cognitive impairment. Previous data indicate that circulating Th17-derived IL17 acts on cerebral endothelial cells to induce a deficit in endothelial nitric oxide (NO) promoting tau accumulation and cognitive impairment. Due to their abundance in the gut, Th17 cells are particularly sensitive to gut bacteria and alterations in the gut flora are associated with dysregulation of Th17 cells. Segmented filamentous bacteria (SFB) are commensal bacteria which potently induce gut Th17 cells in mice and alter the course of models of Th17 cell-associated diseases. Therefore, gut Th17 dysregulation induced by SFB could be used as a model to gain a better mechanistic understanding of how gut Th17 cells alter brain health. On these bases, we propose to test the central hypothesis that dysregulation of gut Th17 cells, induced by colonization of the small intestine with SFB, promotes an IL17-mediated inflammatory response in cerebral endothelial cells which, in turn, activates microglia, leading to tau accumulation and cognitive impairment. To this end, the present grant application will examine endothelial function, tau pathology and cognitive function in a mouse model of SFB colonization to test the following hypotheses in male, female and aging mice: (1) Gut SFB colonization promotes gut Th17 differentiation, increases circulating IL17 and induces cerebrovascular and cognitive impairment; (2) Circulating IL17 mediates cerebrovascular dysfunction and cognitive impairment through activation of brain endothelial IL17 receptors; (3) IL17-induced endothelial pro-inflammatory mediators activate microglia leading to tau accumulation and cognitive impairment. The proposed studies fill an obvious gap in the understanding of the effects of gut microbiota on cognition and of the role of circulating IL17, endothelial cells and microglia in mediating these effects. Furthermore, these findings may unveil a novel link between microbiota-induced dysregulation of intestinal Th17 cells, brain tau accumulation and cognitive impairment, with potential public health implications.