Gut barrier function in Alzheimer’s disease

阿尔茨海默病中的肠道屏障功能

• 批准号: 10350685
• 负责人: Barbara Brigitta Bendlin
• 金额: $ 74.82万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-02-15 至 2026-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10350685
• 关键词: Address; Age; Aging; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease pathology; Alzheimer' s disease related dementia; Alzheimer’s disease biomarker; Amyloid; Amyloid beta-42; Antibody titer measurement; Automobile Driving; Biological Assay; Biological Markers; Blood - brain barrier anatomy; Blood Circulation; Brain; Cerebrospinal Fluid; Chemicals; Clinical; Cognitive; Collection; Derivation procedure; Development; Disease; Disease Progression; Elderly; Enrollment; FRAP1 gene; Gastrointestinal tract structure; Germ-Free; Gnotobiotic; Goals; Homeostasis; Human; Immune response; Immune system; Impairment; Individual; Infrastructure; Innate Immune Response; Intestinal permeability; Intestines; Lactulose; Lead; Leukocyte L1 Antigen Complex; Link; Lipopolysaccharides; Liquid substance; Mannitol; Measures; Mediating; Methods; Microbe; Microbiology; Mucous body substance; Mus; Nerve Degeneration; Neurodegenerative Disorders; Participant; Pathogenesis; Pathology; Permeability; Persons; Play; Positron-Emission Tomography; Process; Publishing; Reporting; Research; Resources; Role; Sampling; Signal Transduction; Sodium Dextran Sulfate; System; Testing; Therapeutic; Time; United States; Wisconsin; Work; age related; amyloid pathology; base; blood-brain barrier permeabilization; cohort; effective therapy; experimental study; gut dysbiosis; gut inflammation; gut microbes; gut microbiome; gut microbiota; indexing; inflammatory marker; intestinal barrier; macromolecule; metagenome; microbial; microbiome composition; mouse model; neuroimmunology; neuropathology; novel therapeutic intervention; prospective; success; systemic inflammatory response; tau Proteins; virtual

The age-related processes that contribute to Alzheimer's disease (AD) development, particularly in the prodromal period, are incompletely understood. Age-related reduction in gut microbiome alpha-diversity is apparent in the majority of older adults, and is suspected of contributing to brain changes, including the development of neurodegenerative disease. Our team published the first comprehensive report describing differences in the gut microbiome observed in AD dementia, including reduced diversity in gut microbiota and altered composition in people with AD dementia compared to age-matched controls. Furthermore, we found that differentially abundant genera were associated with cerebrospinal fluid biomarkers of AD, even among individuals who were cognitively unimpaired. Several studies in mouse models of AD indicate that gut microbiota play a role in the development of AD neuropathology, however to date, the mechanisms underlying these effects are virtually unknown. Recently it has also become clear that the innate immune response in AD plays a critical role in mediating the pathology associated with AD; however the interplay between systemic changes and the innate immune response in AD are not well understood, nor is it known how these factors impact the progression of AD pathology. Our overarching goal is to determine the extent to which alterations in the composition of gut microbiome exacerbate and/or accelerate the development of AD pathology. This proposal is based on the central hypothesis that age-associated gut dysbiosis and inflammation weaken gut barrier function, which in turn leads to the systemic dissemination of microbial components, driving an immune response and system wide changes that worsen AD pathology. To test this hypothesis we propose to study well-characterized participants enrolled in the Wisconsin Alzheimer's Disease Research Center as well as conventional and gnotobiotic APPPS1 mice, to address the following specific aims: 1. Determine the longitudinal relationship between gut microbiome (metagenome), gut inflammation and permeability, and the development of AD pathology in human participants, and 2. Determine the effects of modifying gut permeability on AD pathology in mice. We expect that alterations in gut microbiome composition and gut permeability exacerbate AD pathology in humans, and that impairment of intestinal barrier function and increased gut permeability alters brain homeostasis and exacerbates AD progression in mouse models of AD. Our research group has been working to determine the role of gut microbiome in the development of AD pathology for the past 5 years, and we are perfectly poised to address the proposed aims. We will leverage our expertise in clinical AD, neuroimmunology, and gut microbiology/gnotobiotic mouse models to successfully carry out the proposed project. Completion of the proposed experiments is expected to lead to the development of novel therapeutic strategies for AD and related dementias.

导致阿尔茨海默氏病（AD）发展的与年龄有关的过程，特别是在 前沿时期未完全理解。与年龄相关的肠道微生物组α多样性的减少是 在大多数老年人中都显而易见，并怀疑有助于大脑变化，包括 神经退行性疾病的发展。我们的团队发表了第一份综合报告，描述了 在AD痴呆中观察到的肠道微生物组的差异，包括肠道微生物群的多样性降低 与年龄匹配的对照相比，AD痴呆症患者的组成改变。此外，我们发现 差异丰富的属与AD的脑脊液生物标志物有关，即使 认知没有受损的人。 AD小鼠模型中的几项研究表明肠道菌群 在AD神经病理学的发展中发挥作用，但是迄今为止，这些作用的机制 几乎是未知的。最近，也很清楚，AD中的先天免疫反应起着至关重要的作用 在介导与AD相关的病理学中的作用；但是，全身变化与 AD中的先天免疫反应尚不清楚，也不知道这些因素如何影响进展 广告病理学。我们的总体目标是确定肠道成分的改变程度 微生物组加剧和/或加速AD病理的发展。该建议基于 中心假设是年龄相关的肠道营养不良和炎症会弱化肠道障碍功能 导致微生物成分的全身传播，驱动免疫反应和系统范围 变化加剧了广告病理学。为了检验这一假设，我们建议研究良好的参与者 加入了威斯康星州阿尔茨海默氏病研究中心以及常规和gnotobiotic appps1小鼠，以解决以下特定目的：1。确定肠道之间的纵向关系 微生物组（元基因组），肠炎和渗透性以及AD病理学的发展 人类参与者和2。确定修饰肠道渗透性对小鼠AD病理学的影响。 我们期望肠道微生物组组成和肠道通透性的改变加剧了AD病理学 人类，肠道屏障功能的损害和肠道渗透性增加改变了大脑 AD小鼠模型中的稳态和加剧AD的进展。我们的研究小组一直在工作 确定肠道微生物组在过去5年中的作用中的作用，我们是 完全准备解决拟议的目标。我们将利用我们在临床广告，神经免疫学方面的专业知识， 和肠道微生物学/gnotobiotic小鼠模型成功地执行了提出的项目。完成 预计拟议的实验将导致发展AD和AD的新型治疗策略 相关痴呆症。