Gut Immunity, Neurovascular Dysregulation and Cognitive Impairment

阿尔茨海默病和相关痴呆(ADRDS)是一组与年龄相关的疾病 影响没有治疗方法的认知功能。神经炎症和 神经血管功能障碍已成为ADRDS疾病进展的关键驱动因素。在……里面 特别是，脑内皮细胞和小胶质细胞，大脑固有的免疫细胞，已经被 与过度磷酸化的tau有关，一种微管相关蛋白和 ADRD病理的一个重要特征。外周免疫系统的失调也可能 发挥作用并可能影响内皮细胞和小胶质细胞的功能，有助于认知 减损。然而，外周免疫系统如何与大脑沟通 改变认知功能的微血管和小胶质细胞仍未完全确定。 产生IL17的辅助性T淋巴细胞(Th17细胞)，辅助性T淋巴细胞的一个亚群，以及 他们的标志性细胞因子IL17被认为与认知障碍的机制有关。 先前的数据表明，循环中的Th17来源的IL17作用于脑内皮细胞以 诱导内皮细胞一氧化氮(NO)缺乏促进tau堆积和认知 减损。由于Th17细胞在肠道中含量丰富，因此对肠道细菌特别敏感。 肠道菌群的改变与Th17细胞的失调有关。分段的 丝状细菌(SFB)是一种能诱导小鼠肠道Th17细胞的共生菌 并改变Th17细胞相关疾病模型的进程。因此，Gut Th17 SFB诱导的失调可以作为一种模型来获得更好的机制 了解肠道Th17细胞如何改变大脑健康。在此基础上，我们建议测试 中心假设肠道Th17细胞失调，由小鼠的定植引起 SFB促进IL-17介导的脑内皮细胞炎症反应 细胞反过来激活小胶质细胞，导致tau积累和认知障碍。至 为此，目前的赠款申请将检查内皮功能，tau病理和 在SFB定植的小鼠模型中的认知功能在雄性中测试以下假设， 雌性和老龄小鼠：(1)肠道SFB定植促进肠道Th17分化，增加 循环白介素17，引起脑血管和认知功能障碍；(2)循环白介素17 通过脑激活调节脑血管功能障碍和认知功能障碍 内皮细胞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蓄积和认知障碍。拟议的研究填补了 在对肠道微生物区系对认知的影响以及对肠道微生物区系在认知中的作用的认识上存在明显差距 循环中的IL17、内皮细胞和小胶质细胞参与了这些效应的调节。此外，这些 这些发现可能会揭示微生物群诱导的肠道Th17细胞调节失调之间的新联系， 大脑tau蓄积和认知损害，具有潜在的公共健康影响。

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.