Gut-brain axis in Alzheimer's disease: translational 7T MRI markers and underlying mechanisms

阿尔茨海默病中的肠脑轴：转化 7T MRI 标记物和潜在机制

• 批准号: 10901013
• 负责人: Priti Balchandani
• 金额: $ 81.01万
• 依托单位: UNIVERSITY OF MISSOURI-COLUMBIA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-15 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10901013
• 关键词: 3xTg-AD mouse; Acceleration; Adverse effects; Alzheimer' s Disease; Alzheimer' s disease patient; Alzheimer' s disease risk; Alzheimer’s disease biomarker; Amyloid; Animal Experiments; Animals; Area; Bacteroides; Biochemical; Biological Assay; Brain; Brain region; Cerebrovascular Circulation; Classification; Clinical Trials; Cognition; Cognitive; Data; Dementia; Diet; Disease; Disease Progression; Equilibrium; Escherichia coli; Female; Future; Gene Expression; Goals; Hippocampus; Human; Impaired cognition; Individual; Inflammatory; Intervention; Intervention Studies; Inulin; Knock-out; Knockout Mice; Knowledge; Link; Magnetic Resonance Imaging; Microbe; Mus; NOS2A gene; Nerve Degeneration; Neurofibrillary Tangles; Nitric Oxide Synthetase Inhibitor; Outcome; Participant; Physiology; Positioning Attribute; Positron-Emission Tomography; Pre-Clinical Model; Research Design; Senile Plaques; Severities; Stains; Supplementation; Testing; Transgenic Organisms; Transplantation; Volatile Fatty Acids; brain volume; cognitive function; cognitive testing; design; dietary control; dysbiosis; effective intervention; extracellular; fecal transplantation; gut dysbiosis; gut microbes; gut microbiome; gut-brain axis; human model; human study; imaging biomarker; magnetic resonance imaging biomarker; microbial community; microbiome; microbiome analysis; microbiome composition; microbiome sequencing; microbiota; mouse model; multimodality; neuroimaging marker; neuroinflammation; neuropathology; neuroprotection; novel; pathogenic bacteria; pre-clinical; prebiotics; recruit; sex; stool sample; success; tau Proteins; transcriptomics; translational study; ultra high resolution; white matter

Project Summary Alzheimer’s disease (AD) is the most common form of dementia with hallmarks of extracellular beta amyloid (Aβ) plaques (A), intraneuronal tau tangles (T), and neurodegeneration (N), known as the A/T/N framework, a descriptive classification for AD biomarkers. Accumulating evidence shows that a severely imbalanced microbial community, or dysbiosis, is associated with A/T/N and neuroinflammation in AD patients compared with healthy controls (HC). However, it remains unknown how individual microbiota correlates with regional A/T/N neuroimaging markers in AD and HC. It is also unknown if dysbiosis directly promotes and accelerates A/T/N at early stage and whether there are effective interventions available to mitigate the dysbiosis and thus AD risk. Therefore, the goal of the project is to design a translational study, employing parallel human and preclinical animal experiments to understand mechanism and identify interventions for filling these knowledge gaps. The central hypothesis is that severity of dysbiosis between AD and HC individuals will correlate with their regional A/T/N imaging markers and cognitive status; young healthy triple transgenic AD (3xTg-AD) mice received fecal microbiome transplantation (FMT) from AD patients (FMT-AD) will have reproduced dysbiosis as the donors, which will accelerate A/T/N, neuroinflammation and cognitive impairment of the mice. Interventions with inducible nitric oxide synthase (iNOS) inhibition will mitigate A/T/N and neuroinflammation, and prebiotic diet (inulin) supplementation can further restore microbiome balance to protect brain physiology and cognition. The central hypothesis will be tested by the following three Specific Aims: (1) Identify correlation of dysbiosis, A/T/N imaging markers and cognition in humans; (2) Reveal impact of iNOS on mitigating A/T/N in the presence of dysbiosis; (3) Determine ability of inulin, with and without functional iNOS, to rescue FMT-AD- induced A/T/N and cognitive impairment. Participants who had PET scans for “A/T” will be recruited for the study, and ultrahigh resolution 7T MRI will be used to determine “N”. Translational 7T MRI, gut microbiome sequencing and cognitive assessments will be applied to both humans and mice to determine longitudinal effects of gut-brain interactions. A novel iNOS knockout triple transgenic AD (iNOS-KO/3xTg-AD) mouse model has been created for the project to study the iNOS effects on mitigating A/T/N despite of gut dysbiosis. Biochemical assays and brain staining will be used to determine “A/T” in the mice. Inflammatory gene expression will be identified by transcriptomics. It is anticipated that the findings from this study will have tremendous positive impact as they will enhance the understanding of gut-brain interactions underlying A/T/N in AD and pave the way for future disease-modifying interventions for AD via the microbiome-gut-brain axis. As iNOS inhibitors, inulin diet, 7T MRI and microbiome analyses are available for humans, the success of animal interventional outcomes and the human study pipeline established in the study may pave a way for future clinical trials to mitigate AD risk by gut microbiome modulation.

项目摘要 阿尔茨海默病(AD)是最常见的痴呆形式，具有细胞外β淀粉样蛋白的特征 (aβ)斑块(A)、神经元内tau缠结(T)和神经变性(N)，称为A/T/N框架，a AD生物标志物的描述性分类。越来越多的证据表明，一个严重失衡的 比较AD患者的微生物群落或生物失调与A/T/N和神经炎症的关系 健康对照组(HC)。然而，目前还不清楚单个微生物区系如何与区域 AD和HC的A/T/N神经影像标志物。生物失调是否直接促进和加速也是未知的。 A/T/N在早期阶段，以及是否有有效的干预措施来缓解生物失调，从而 广告风险。因此，该项目的目标是设计一项翻译研究，使用平行人类和 临床前动物实验，以了解机制并确定填补这些知识的干预措施 差距。中心假设是AD和HC患者之间的生物失调的严重程度将与 青年健康三重转基因AD(3xTg-AD)小鼠局部A/T/N影像标志物与认知状态的关系 接受AD患者粪便微生物组移植(FMT-AD)后，将产生 供者会加速A/T/N、神经炎症和认知功能障碍。干预措施 通过抑制诱导型一氧化氮合酶(INOS)将减轻A/T/N和神经炎症，以及益生菌 补充饮食(菊粉)可进一步恢复微生物群平衡，保护大脑生理和认知。 中心假说将通过以下三个具体目标进行检验：(1)确定生物失调的相关性， A/T/N影像标志物与人类认知；(2)揭示iNOS在缓解A/T/N中的作用 (3)确定菊粉在有和没有功能性iNOS的情况下拯救FMT-AD-的能力。 诱发A/T/N和认知功能障碍。接受正电子发射计算机断层扫描检查“A/T”的参与者将被招募参加 研究中，将使用超高分辨率7T磁共振来确定N。翻译7T磁共振，肠道微生物组 测序和认知评估将应用于人类和小鼠，以确定纵向 肠道-大脑相互作用的影响。一种新型iNOS基因敲除三重转基因AD(iNOS-KO/3xTg-AD)小鼠 本项目已经建立了模型，以研究iNOS在缓解A/T/N方面的作用，尽管存在肠道生物失调。 生化分析和脑染色将用来确定小鼠的“A/T”。炎性基因 表达将通过转录组学进行鉴定。预计这项研究的结果将具有 巨大的积极影响，因为它们将加强对A/T/N背后的肠道-大脑相互作用的理解 并为未来通过微生物-肠道-脑轴对AD进行疾病改良干预铺平道路。AS INOS抑制剂、菊粉饮食、7T核磁共振和微生物组分析可用于人类，动物的成功 干预结果和研究中建立的人体研究管道可能为未来铺平道路 通过肠道微生物群调节降低AD风险的临床试验。