Microbiome-microglia interactions in Alzheimer’s disease pathophysiology

阿尔茨海默病病理生理学中微生物组与小胶质细胞的相互作用

• 批准号: 10679850
• 负责人: Lisa Blackmer-Raynolds
• 金额: $ 4.77万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-05-03 至 2025-05-02
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10679850
• 关键词: Acceleration; Affect; Alzheimer like pathology; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease pathology; Alzheimer' s disease patient; Amyloid; Amyloid beta-Protein; Bacteria; Bacteroidaceae; Bacteroides thetaiotaomicron; Behavioral; Brain; Brain Pathology; Caregivers; Cell Communication; Cells; Clinical Trials; Cognition; Cognitive; Communication; Data; Data Set; Dementia; Development; Disease; Disease Outcome; Disease Progression; Enterobacteriaceae; Escherichia coli; Etiology; Failure; Functional disorder; Gene Expression; Genetic Transcription; Germ-Free; Gnotobiotic; Health; Immune; Immune signaling; Impaired cognition; Individual; Inflammation; Inflammatory; Inflammatory Response; Lactobacillus; Link; Macrophage; Mediating; Microbe; Microglia; Modeling; Molecular Biology; Mus; National Research Service Awards; Nervous System Physiology; Neuroimmune; Neurons; Neurosciences; Outcome; Pathologic; Pathology; Pathway interactions; Patients; Peripheral; Persons; Phagocytes; Public Health; Research; Risk Factors; Role; Shapes; Signal Transduction; Symptoms; System; Techniques; Testing; Time; Tissues; Training; United States; Wild Type Mouse; abeta accumulation; career; cell type; cytokine; disorder risk; dysbiosis; functional outcomes; gut bacteria; gut dysbiosis; gut microbes; gut microbiome; immunoregulation; improved; inflammatory modulation; innovation; insight; interdisciplinary approach; microbial; microbial colonization; microbiome; microbiome composition; monocyte; mouse model; mutant; neuroinflammation; neuropathology; neurotoxicity; neurotransmission; novel; pharmacologic; response; single nucleus RNA-sequencing; stem; tau Proteins; therapeutically effective; transcriptomics; transmission process

Project Summary: Alzheimer’s disease (AD) is a growing public health threat that places an immense burden on patients, caregivers, and the economy. Despite a century of research and over 2,000 clinical trials, AD has limited treatment options and no cure. The failure to develop effective therapeutics likely stems from an incomplete understanding of AD etiology—highlighting the crucial need to identify and better understand modifiable disease risk factors. Recent evidence suggests that, in addition to brain pathology, AD patients also display alterations in the gut microbiome that may contribute to disease. Manipulation of the gut microbiome is sufficient to improve or exacerbate AD-like symptoms and pathology in mouse models, suggesting that the microbiome may directly contribute to disease development and progression. The mechanism by which the microbiome impacts disease etiology is currently unknown, however, one possibility is through modulation of inflammatory responses. The gut microbiome has been shown to influence the development and activation states of both peripheral and brain- resident immune cells that are critical for amyloid clearance and neuronal health. However, the contribution of individual AD-associated microbial species to neuroinflammatory and disease outcomes is unknown, and the mechanisms of this gut-to-brain communication have yet to be explored. The present NRSA will address this gap, determining the consequences of, and mechanisms by which, specific AD-associated gut microbes shape neuroinflammatory and disease outcomes. Aim 1 will establish the effects of individual AD-associated gut microbes on microglia functional state and response to stimulation (1.1). Furthermore, it will determine whether these gut-to-brain signals are mediated by specific peripheral immune signals triggered by discrete bacterial molecules (1.2). Aim 2 will concurrently determine the pathophysiological impacts of specific AD-associated bacteria on disease outcomes (2.1) and evaluate whether microglia and specific bacterial inflammogens are necessary for these effects. This innovative, interdisciplinary approach will provide key mechanistic links between gut dysbiosis and AD outcomes. In addition, by identifying both microbe and host-derived cellular pathways that impact disease state, it will identify novel and specific treatment targets for AD.

项目摘要： 阿尔茨海默氏病（AD）是日益增长的公共卫生威胁，对患者造成了巨大的烧伤， 照顾者和经济。尽管进行了一个世纪的研究和2,000多次临床试验，但AD仍有限 治疗选择，没有治疗方法。未能开发有效疗法的可能是从不完整的 了解AD病因 - 高显示识别和更好地理解可修改疾病的关键需求 风险因素。最近的证据表明，除了大脑病理外，AD患者还显示出改变 在可能导致疾病的肠道微生物组中。肠道微生物组的操纵足以改善 或恶化小鼠模型中类似广告样的症状和病理学，表明微生物组可能直接 对疾病发展和进展的贡献。微生物组影响疾病的机制 但是，病因目前尚不清楚，但一种可能性是通过调节炎症反应。 肠道微生物组已被证明会影响外周和脑的发育和激活态 对淀粉样蛋白清除和神经元健康至关重要的居民免疫核管。但是， 单个与AD相关的微生物物种与神经炎症和疾病结局是未知的，并且 这种肠道沟通的机制尚未探索。目前的NRSA将解决这个问题 差距，确定特定广告相关的肠道微生物的后果和机制的后果和机制 神经炎症和疾病结局。 AIM 1将建立单个与广告相关的肠道的影响 小胶质细胞功能状态的微生物和对刺激的反应（1.1）。此外，它将决定是否 这些直至脑的信号是由离散细菌触发的特定外周免疫信号介导的 分子（1.2）。 AIM 2将同时确定特定AD相关的病理生理影响 疾病结局细菌（2.1），并评估小胶质细胞和特定细菌炎症是 这些效果所必需的。这种创新的跨学科方法将提供关键的机械链接 在肠道营养不良和AD结局之间。另外，通过识别微生物和宿主衍生的细胞 影响疾病状态的途径，它将确定AD的新颖和特定治疗靶标。