Gut Immunity, Neurovascular dysregulation and Cognitive Impairment

肠道免疫、神经血管失调和认知障碍

• 批准号: 10567542
• 负责人: Giuseppe Faraco
• 金额: $ 42.38万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-18 至 2027-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10567542
• 关键词: Affect; Aging; Alzheimer' s Disease; Alzheimer' s disease related dementia; Amyloid beta-Protein; Animal Model; Applications Grants; Bacteria; Blood; Brain; Cells; Cerebrovascular Disorders; Clinical; Cognition; Cognitive; Communication; Data; Dementia; Disease; Disease Progression; Endothelial Cells; Endothelium; Female; Functional disorder; Helper-Inducer T-Lymphocyte; Homeostasis; Human; IL17 gene; Immune; Immune system; Immunity; Impaired cognition; Inflammation; Inflammation Mediators; Inflammatory; Inflammatory Response; Intestines; Link; Maintenance; Mediating; Microglia; Microtubule-Associated Proteins; Microtubules; Modeling; Morbidity - disease rate; Mus; Nitric Oxide; Pathologic; Pathology; Patients; Peripheral; Play; Public Health; Regulation; Risk; Role; Sex Differences; Signal Transduction; Small Intestines; Testing; age group; age related; base; brain cell; brain endothelial cell; brain health; cardiovascular risk factor; cerebral microvasculature; cerebrovascular; cognitive development; cognitive function; commensal bacteria; cytokine; dietary salt; gut bacteria; gut microbiota; hyperphosphorylated tau; inflammatory marker; male; member; microbiota; mortality; mouse model; neuroinflammation; neurovascular; neutralizing antibody; novel; pre-clinical; receptor; response; tau Proteins; tau aggregation

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.

阿尔茨海默氏病和相关痴呆症（ADRDS）是一组与年龄有关的疾病 影响没有可用治疗的认知功能。神经炎症和 神经血管功能障碍已成为ADRD中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，脑居民先天免疫细胞一直是 在磷酸化tau，微管相关蛋白和 ADRD病理学的关键特征。外周免疫系统的失调也可能 发挥作用并可能影响内皮和小胶质细胞功能，有助于认知 损害。但是，外周免疫系统如何与大脑通信 微举行的微胶质细胞和小胶质细胞改变认知功能尚待完全确定。 产生IL17的T助血淋巴细胞（Th17细胞），T-助血淋巴细胞的子集和 它们的签名细胞因子IL17与认知障碍的机制有关。 以前的数据表明，循环Th17衍生的IL17作用于脑内皮细胞 诱发内皮一氧化氮（NO）的赤字，促进tau积累和认知 损害。由于肠道中的丰富性，Th17细胞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 丝状细菌（SFB）是共生细菌，可能诱导小鼠肠道Th17细胞 并改变Th17细胞相关疾病的模型的过程。因此，肠道Th17 SFB诱导的失调可以用作模型，以获得更好的机理 了解肠道Th17细胞如何改变脑健康。在这些基础上，我们建议测试 中心假设是肠道Th17细胞的失调，由小的定植引起 带有SFB的肠，促进脑内皮的IL17介导的炎症反应 细胞反过来激活小胶质细胞，从而导致tau积累和认知障碍。到 在此目前，目前的赠款申请将检查内皮功能，tau病理学和 SFB定殖的小鼠模型中的认知功能，以测试男性的以下假设 雌性和衰老小鼠：（1）肠道SFB定殖促进肠道Th17分化，增加 循环IL17并诱导脑血管和认知障碍； （2）循环IL17 通过激活大脑介导脑血管功能障碍和认知障碍 内皮IL17受体； （3）IL17引起的内皮促炎介质激活 小胶质细胞导致tau积累和认知障碍。拟议的研究充满了 在理解肠道微生物群对认知和认知作用的作用方面的明显差距 循环IL17，内皮细胞和小胶质细胞介导这些作用。此外，这些 发现可能会揭示微生物群引起的肠道Th17细胞失调的新型联系， 大脑tau的积累和认知障碍，潜在的公共卫生影响。