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

基本信息

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
项目类别：
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&apos s Disease Alzheimer&apos s disease model Alzheimer&apos s disease pathology Alzheimer&apos 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

项目摘要

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.

项目概要：阿尔茨海默病（AD）是一种日益严重的公共卫生威胁，给患者带来巨大负担，尽管经过一个世纪的研究和 2,000 多项临床试验，AD 的效果仍然有限。未能开发出有效的治疗方法可能源于不完整的治疗选择。了解 AD 病因——强调识别和更好地了解可改变疾病的迫切需要最近的证据表明，除了大脑病理学之外，AD 患者还表现出改变。肠道微生物组中可能导致疾病的因素，操纵肠道微生物组足以改善。或加剧小鼠模型中的 AD 样症状和病理，这表明微生物组可能直接微生物组影响疾病的机制。目前病因尚不清楚，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大脑的发育和激活状态然而，对于淀粉样蛋白清除和神经元健康至关重要的常驻免疫细胞。个别 AD 相关微生物物种对神经炎症和疾病结果的影响尚不清楚，并且目前的 NRSA 将解决这一问题。差距，确定特定 AD 相关肠道微生物形成的后果和机制目标 1 将确定个体 AD 相关肠道的影响。微生物对小胶质细胞功能状态和对刺激的反应此外，它将决定是否。这些肠道到大脑的信号是由离散细菌触发的特定外周免疫信号介导的目标 2 将同时确定特定 AD 相关的病理生理学影响。细菌对疾病结果的影响 (2.1) 并评估小胶质细胞和特定细菌炎症原是否这种创新的跨学科方法将提供关键的机械联系。此外，通过识别微生物和宿主来源的细胞来了解肠道菌群失调和AD结果之间的关系。它将确定影响疾病状态的途径，从而确定 AD 的新颖且具体的治疗目标。