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 阿尔茨海默氏病（AD）是最常见的痴呆形式，具有细胞外β淀粉样蛋白的标志 （Aβ）斑块（a），神经内神经内tau缠结（t）和神经变性（n），称为a/t/n框架，a 广告生物标志物的描述性分类。积累的证据表明，严重失衡 与AD患者相比 具有健康对照（HC）。但是，单个微生物群与区域的相关性仍然未知 AD和HC中的A/T/N神经成像标记。尚不清楚营养不良是否直接促进和加速 早期的A/T/N以及是否有有效的干预措施来减轻营养不良，因此 广告风险。因此，该项目的目的是设计一项翻译研究，采用平行人类和 临床前动物实验以了解机制并确定填充这些知识的干预措施 空白。中心假设是，AD和HC个体之间营养不良的严重程度将与 他们的区域A/T/N成像标记和认知状态；年轻的健康三重转基因AD（3XTG-AD）小鼠 从AD患者（FMT-AD）接受的粪便微生物组移植（FMT）将再现了营养不良的疾病 这些捐赠者将加速A/T/N，小鼠的神经炎症和认知障碍。 诱导一氧化氮合酶（INOS）抑制作用将减轻A/T/N和神经炎症，并益生元 补充饮食（菊粉）可以进一步恢复微生物组的平衡，以保护脑生理和认知。 中心假设将通过以下三个特定目的进行检验：（1）确定失调的相关性， 人类的A/T/N成像标记和认知； （2）揭示了iNOS对缓解A/T/N的影响 营养不良的存在； （3）确定菊粉，有或没有功能iNOS的能力，可以挽救FMT-AD-AD- 诱导的A/T/N和认知障碍。对“ A/T”进行PET扫描的参与者将被招募 研究和超高分辨率7T MRI将用于确定“ n”。翻译7T MRI，肠道微生物组 测序和认知评估将用于人类和小鼠，以确定纵向 肠道相互作用的影响。一种新型的iNOS基因敲除三重转基因AD（iNOS-KO/3XTG-AD）小鼠 已经为该项目创建了模型，以研究iNOS对减轻肠道营养不良的A/T/N目的地的影响。 生化测定和大脑染色将用于确定小鼠的“ A/T”。炎症基因 表达式将通过转录组学识别。预计这项研究的发现将有 巨大的积极影响，因为它们将增强对A/T/N为基础的肠脑相互作用的理解 在AD和AD铺平道路上，通过微生物组 - 脑轴轴对AD进行了未来的疾病修改干预措施。作为 iNOS抑制剂，菊粉饮食，7T MRI和微生物组分析可用于人类，动物的成功 研究中建立的介入结果和人类研究管道可能会为未来铺平一种方式 通过肠道微生物组调节来减轻AD风险的临床试验。