Microbial dysbiosis as a driver of neuroinflammation and pathology in Alzheimer's disease

摘要 最近的进展有助于揭示肠道微生物群在一系列神经系统疾病中的关键作用 包括许多神经退行性疾病。在阿尔茨海默病（AD）的情况下，它已被证明在两个 AD患者和动物模型表明，神经退行性疾病进展与大规模的 肠道微生物群组成的变化。此外，最近的数据还表明， 无论是无菌再衍生还是用广谱抗生素长期治疗， 过表达淀粉样蛋白β（Ab）的小鼠。虽然这些发现引起了对潜在作用的兴奋， 尽管AD中存在微生物生态失调，但关于该主题的许多基本问题仍有待回答。首先， 所有这些先前的研究仅探索了鼠微生物组对神经退行性疾病的影响。 目前还没有研究在AD患者中观察到的特定生态失调如何影响神经系统疾病 进展鉴于小鼠和人类微生物组之间存在的主要差异， 重要的是要专门探讨人类肠道微生物群的改变如何影响神经退行性疾病 流程.此外，目前对微生物生态失调如何影响tau蛋白病知之甚少。填补这些 我们将从AD患者或年龄和性别匹配的对照组中移植肠道微生物群， 无菌3xTg-AD小鼠，这是一种描述良好的AD小鼠模型，其发展与年龄相关的， 进行性Ab诱导的神经系统疾病和tau蛋白病。人类AD相关的生态失调对 然后通过评估Ab沉积、tau蛋白病、神经变性 神经炎症和认知表现（目标1）。其他非AD模型的最新研究 神经退行性疾病表明，肠道微生物群可以通过调节 免疫系统和/或通过促进代谢物产生的变化。因此，在第二个目标中，我们 下一步将利用尖端的单细胞RNA测序（scRNA-seq）和代谢组学方法， 对AD相关的生态失调如何影响免疫反应提供全面和公正的评估 和代谢组在我们的人类微生物群移植AD小鼠模型。我们的首要假设是 AD患者的微生物生态失调导致神经退行性疾病恶化， 这与免疫反应和代谢组的失调有关。成功完成这些 拟议的研究方向将为我们对AD相关生态失调的作用的理解开辟新天地 并将开始揭示支持神经退行性疾病发病机制的前瞻性因素。 人类AD微生物组对疾病进展的影响。此外，这些研究的结果是 潜在的翻译意义，因为它们可以帮助建立微生物组作为治疗靶点， 在AD的治疗中。

ABSTRACT Recent advances have helped to uncover critical roles for gut microbiota in a spectrum of neurological disorders including many neurodegenerative diseases. In the case of Alzheimer’s disease (AD), it has been shown in both AD patients and animal models that neurodegenerative disease progression is associated with large-scale changes in gut microbiota composition. Moreover, recent data also suggest that ablation of the microbiome with either germ-free re-derivation or chronic treatment with broad-spectrum antibiotics water limits amyloidosis in mice that over-express amyloid beta (Ab). While these findings have led to excitement over the potential role for microbial dysbiosis in AD, numerous fundamental questions still remain to be answered on this topic. For one, all of these previous studies have only explored the impact of the murine microbiome on neurodegenerative disease and have not investigated how the specific dysbiosis seen in AD patients affects neurological disease progression. Given the major differences that exist between the mouse and human microbiome, it will be important to specifically probe how alterations in human gut microbiota influence neurodegenerative disease processes. In addition, little is currently known regarding how microbial dysbiosis affects tauopathy. To fill these gaps in knowledge, we will transplant gut microbiota from either AD patients or age- and sex-matched controls into germ-free 3xTg-AD mice, which is a well-described mouse model of AD that develops age-related and progressive Ab-induced neurological disease and tauopathy. The impact of human AD-associated dysbiosis on disease progression will then be determined by evaluating Ab deposition, tauopathy, neurodegeneration, neuroinflammation, and cognitive performance (Aim 1). Recent studies in other non-AD models of neurodegenerative disease suggest that the gut microbiota can influence disease progression via modulation of the immune system and/or by promoting changes in metabolite generation. Therefore, in our second Aim, we will next leverage cutting-edge single-cell RNA-sequencing (scRNA-seq) and metabolomics approaches to provide a comprehensive and unbiased assessment of how AD-associated dysbiosis affects immune responses and the metabolome in our human microbiota transplantation AD mouse model. Our overarching hypothesis is that microbial dysbiosis in AD patients leads to exacerbated neurodegenerative disease progression and that this is associated with dysregulation of immune responses and the metabolome. Successful completion of these proposed research directions will break new ground in our understanding of the role of AD-associated dysbiosis in neurodegenerative disease pathogenesis and will also begin to reveal prospective factors underpinning the effects of the human AD microbiome on disease progression. Furthermore, findings from these studies are of potential translational significance as they could help to establish the microbiome as a therapeutic target to pursue in the treatment of AD.