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

微生物失调是阿尔茨海默病神经炎症和病理的驱动因素

• 批准号: 10370667
• 负责人: John R Lukens
• 金额: $ 43.47万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-02-15 至 2024-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10370667
• 关键词: 3xTg-AD mouse; Ablation; Address; Affect; Age; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease patient; Amyloid beta-Protein; Amyloidosis; Animal Model; Antibiotics; Atlases; Biological Factors; Brain; Brain Pathology; Chronic; Clinical Research; Communities; Data; Derivation procedure; Disease; Disease Progression; Future; Generations; Germ-Free; Human; Human Microbiome; Immune; Immune response; Immune system; Immunity; Knowledge; Laboratories; Mus; Nerve Degeneration; Neurodegenerative Disorders; Pathogenesis; Pathology; Peripheral; Probiotics; Process; Production; Research; Role; Sampling; Serum; Severity of illness; Splenocyte; Study models; Tauopathies; Testing; Transplantation; Water; Work; abeta deposition; age related; cognitive performance; cost effective; dysbiosis; fecal microbiota; fecal transplantation; germ free condition; gut microbiota; human microbiota; human model; immunoregulation; liquid chromatography mass spectrometry; metabolome; metabolomics; microbial; microbiome; microbiota; microbiota transplantation; mouse model; nervous system disorder; neuroinflammation; overexpression; prospective; reconstitution; sex; single-cell RNA sequencing; therapeutic target; translational potential

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.

摘要 最近的进展有助于揭示肠道微生物区系在一系列神经疾病中的关键作用 包括许多神经退行性疾病。在阿尔茨海默病(AD)的病例中，它在两种疾病中都有表现 AD患者和动物模型表明神经退行性疾病的进展与大规模 肠道微生物区系组成的变化。此外，最近的数据还表明，用 无菌再衍生或用广谱抗生素慢性治疗限制淀粉样变性 过度表达淀粉样β蛋白的小鼠。虽然这些发现让人们对的潜在角色感到兴奋 在阿尔茨海默病中，许多根本性的问题仍有待回答。首先， 所有这些以前的研究都只探讨了小鼠微生物组对神经退行性变的影响 疾病，还没有调查在AD患者中看到的特定的生物失调如何影响神经疾病 进步。考虑到老鼠和人类微生物群之间存在的主要差异，它将是 有必要专门研究人类肠道微生物区系的变化如何影响神经退行性疾病 流程。此外，目前对微生物失调如何影响直立面病知之甚少。为了填满这些 在知识空白方面，我们将移植AD患者或年龄和性别匹配的对照组的肠道微生物区系 转化为无菌3xTg-AD小鼠，这是一种广为人知的AD小鼠模型，其发展与年龄相关和 进行性抗体诱导的神经系统疾病和互补性疾病。人类阿尔茨海默病相关的生物失调对 疾病进展将通过评估抗体沉积、紧张性病变、神经变性、 神经炎症和认知能力(目标1)。其他非AD模型的最新研究进展 神经退行性疾病提示肠道微生物区系可以通过调节 免疫系统和/或通过促进代谢物生成的变化。因此，在我们的第二个目标中，我们 接下来将利用尖端的单细胞RNA测序(scRNA-seq)和代谢组学方法来 对AD相关的生物失调如何影响免疫反应提供全面和公正的评估 以及我们人类微生物区系移植AD小鼠模型中的代谢组。我们最重要的假设是 AD患者的微生物失调导致神经退行性疾病进展加剧， 这与免疫反应和代谢物的失调有关。成功完成这些任务 提出的研究方向将为我们理解AD相关的生物失调的作用开辟新的天地 神经退行性疾病的发病机制，也将开始揭示支持 人类阿尔茨海默病微生物群对疾病进展的影响。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 在阿尔茨海默病的治疗上追求。