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

项目摘要 阿尔茨海默病（AD）是最常见的痴呆形式，其特征在于细胞外β淀粉样蛋白 （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， AD生物标志物的描述性分类。越来越多的证据表明， 微生物群落或微生态失调与AD患者的A/T/N和神经炎症相关， 健康对照组（HC）。然而，个体微生物群与区域微生物群之间的关系仍然未知。 AD和HC中的A/T/N神经影像学标志物。也不知道生态失调是否直接促进和加速了 是否有有效的干预措施来缓解生态失调， AD风险。因此，该项目的目标是设计一个翻译研究，采用平行的人类和 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个体之间的生态失调的严重程度将与 其区域A/T/N成像标记物和认知状态;年轻健康的三重转基因AD（3xTg-AD）小鼠 接受来自AD患者的粪便微生物组移植（FMT）（FMT-AD）将再现生态失调， 这将加速小鼠的A/T/N、神经炎症和认知障碍。干预措施 诱导型一氧化氮合酶（iNOS）抑制剂将减轻A/T/N和神经炎症， 饮食（菊粉）补充可以进一步恢复微生物组平衡，以保护大脑生理和认知。 中心假设将通过以下三个具体目标进行检验：（1）确定生态失调的相关性， 人类中的A/T/N成像标志物和认知;（2）揭示iNOS对减轻A/T/N的影响， （3）测定菊粉在有和没有功能性iNOS的情况下拯救FMT-AD-1的能力。 诱发A/T/N和认知障碍。将招募接受PET扫描“A/T”的参与者， 研究，并将使用高分辨率7 T MRI来确定“N”。平移7 T MRI，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 肠脑互动的影响。一种新的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，以研究尽管肠道生态失调，iNOS对减轻A/T/N的作用。 将使用生化测定和脑染色来确定小鼠中的“A/T”。炎症基因 将通过转录组学鉴定表达。预计这项研究的结果将具有 巨大的积极影响，因为它们将增强对A/T/N背后的肠-脑相互作用的理解 并为未来通过微生物组-肠-脑轴对AD进行疾病修饰干预铺平道路。作为 iNOS抑制剂，菊粉饮食，7 T MRI和微生物组分析可用于人类，动物实验的成功 该研究中建立的介入结果和人类研究管道可能为未来的研究铺平道路。 通过肠道微生物组调节减轻AD风险的临床试验。

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.