Role of IgA-biome in intestinal dysbiosis and brain changes in Alzheimer's disease

总结 据估计，美国有620万人患有阿尔茨海默病（AD），预计将增加近三倍 到2050年虽然遗传和几个环境因素有助于解释AD的病因， 认识到改变的多样性，丰度和肠道组成之间的显着关联， 微生物群、肠功能障碍、上皮屏障完整性的丧失和AD的进展。但据 很难区分关联和因果关系。尽管如此，很明显， 微生物群落消除了延伸到肠道系统之外的炎症特征，并刺激异常的 和大脑病理变化肠道内环境的稳定依赖于分泌的伊加，其覆盖病原菌 并阻断它们与上皮受体的接触以避免炎症反应。我们将检验 IgA包被的细菌（IgA-生物群系）在微生态失调的肠道是致病性的，并负责直接 AD的增强。我们使用AD转基因AppNL-G-F小鼠模型的初步数据表明， 雌性小鼠中IgA包被的粪便细菌水平显著增加。此外，16 s rRNA测序 来自12月龄雌性AppNL-G-F和C57 BL/6野生型小鼠的伊加分选细菌（IgA-seq）的鉴定 伊加包被的微生物类群的明显差异。这些数据伴随着行为改变 仅在雌性AppNL-G-F小鼠中观察到，表明IgA-生物群系、肠道和大脑之间存在联系。全面 通过目标一中的IgA-seq表征IgA生物群系中的纵向变化，并确定是否存在明显的 伊加包被的细菌与免疫表型、记忆、神经胶质增生和β-淀粉样蛋白的变化相关 积累在目的二中，我们将通过口服灌胃转移IgA来验证伊加在生态失调的AD肠道中的作用。 IgA-生物群系从老年小鼠到年轻小鼠，并评估行为、神经胶质增生、神经胶质瘤和神经胶质瘤的性别和基因型依赖性变化。 淀粉样蛋白积聚以及外周和肠免疫调节变化。我们的工作将提供一个新的 了解IgA生物群系作为AD脑变化的贡献者，并可能与其他 神经退行性疾病我们还将确定IgA生物群分类群的独特年龄和疾病模式， 可能是潜在的诊断生物标志物和治疗靶点。

Summary An estimated 6.2 million individuals have Alzheimer’s disease (AD) in the US, which is projected to nearly triple by 2050. Although genetic and several environmental factors help explain the etiology of AD, emerging reports recognize significant associations between altered diversity, abundance, and composition of the intestinal microbiota, intestinal dysfunction, loss of epithelial barrier integrity, and the progression of AD. However, it is difficult to distinguish associations from causal relationships. Nevertheless, it is apparent that the dysbiotic gut microbial community elicits inflammatory features extending beyond the enteric system and stimulates aberrant and pathological brain changes. Intestinal homeostasis relies on secreted IgA that coats pathogenic bacteria and blocks their contact with epithelial receptors to avert inflammatory responses. We will test the idea that IgA-coated bacteria (IgA-biome) in the dysbiotic intestine are pathogenic and responsible for the direct potentiation of AD. Our preliminary data using a transgenic AppNL-G-F mouse model of AD demonstrated a significant increase in the levels of IgA-coated fecal bacteria in female mice. Moreover, 16s rRNA sequencing of IgA sorted bacteria (IgA-seq) from 12-month-old female AppNL-G-F and C57BL/6 wild-type mice identified distinct differences in the microbial taxa coated by IgA. These data were concomitant with behavior changes seen only in the female AppNL-G-F mice suggesting a nexus between the IgA-biome, gut, and brain. We will fully characterize the longitudinal changes in the IgA-biome by IgA-seq in Aim one and determine whether distinct IgA coated bacteria correlate with changes in immune phenotype, memory, gliosis, and -amyloid accumulation. In Aim two, we will validate the role of IgA in the dysbiosed AD gut by oral gavage transfer of IgA-biome from old into young mice and assess sex and genotype-dependent changes in behavior, gliosis, - amyloid accumulation, and peripheral and intestinal immunomodulatory changes. Our work will provide a new understanding of the IgA-biome as a contributor to brain changes in AD and may be relevant to other neurodegenerative conditions. We will also identify the unique age and disease patterns of IgA-biome taxa that can be potential diagnostic biomarkers and therapeutic targets.