Gut barrier function in Alzheimer’s disease

导致阿尔茨海默病(AD)发展的年龄相关过程，特别是在 前驱期，都是不完全了解。与年龄相关的肠道微生物群α多样性降低是 在大多数老年人中都很明显，并被怀疑导致了大脑的变化，包括 神经退行性疾病的发展。我们的团队发布了第一份全面的报告，描述了 在AD痴呆患者中观察到的肠道微生物群的差异，包括肠道微生物区系和 与年龄匹配的对照组相比，AD痴呆症患者的成分发生了变化。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，甚至在 认知能力未受损的个人。对阿尔茨海默病小鼠模型的几项研究表明，肠道微生物区系 在AD神经病理学的发展中发挥作用，然而，到目前为止，这些影响的机制 几乎是未知的。最近也清楚地表明，AD的先天免疫反应在其中起着至关重要的作用 在与AD相关的病理中的作用；然而，系统性变化和 AD的先天免疫反应还不是很清楚，也不知道这些因素是如何影响进展的 AD病理学的研究。我们的首要目标是确定肠道成分的变化程度 微生物组可加重和/或加速AD的病理发展。这项建议是基于 中心假设与年龄相关的肠道生物失调和炎症会削弱肠道屏障功能，进而削弱肠道屏障功能。 导致微生物成分的系统性传播，推动免疫反应和整个系统 使AD病理恶化的变化。为了验证这一假设，我们建议研究特征良好的参与者。 加入威斯康星州阿尔茨海默病研究中心，以及传统和灵知生物 APPPS1小鼠，针对以下具体目的：1.确定肠道的纵向关系 微生物组(超基因组)、肠道炎症和通透性与AD的病理发展 2.确定改变肠道通透性对小鼠AD病理的影响。 我们预计肠道微生物组组成和肠道通透性的改变会加剧AD的病理。 肠道屏障功能受损和肠道通透性增加会改变大脑 在阿尔茨海默病小鼠模型中，动态平衡和加剧阿尔茨海默病的进展。我们的研究小组一直在努力 以确定肠道微生物群在过去5年AD病理发展中的作用，我们正在 完全准备好实现拟议的目标。我们将利用我们在临床AD、神经免疫学、 并成功开展了肠道微生物学/灵芝小鼠模型的拟议项目。完成 拟议的实验有望导致开发AD和AD的新治疗策略 相关痴呆症。

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.