New mechanistic insights into how the gut metabolite urolithin A extends lifespan and prevents AD

项目概要/摘要 该奖项旨在评估肠道代谢产物尿石素A的潜在神经保护作用 (UA)在阿尔茨海默病（AD）的3xAD Tg模型中。补助金的目标3基于以下假设： 减少与年龄相关的肠道微生物群，参与从其膳食前体鞣花酸产生UA 可能导致与3xAD模型相关的神经病理学增加，并可通过 恢复更年轻的微生物组。 除了对神经元的直接影响（父母资助的主题），UA还可能具有 通过其维持肠道完整性和功能的能力产生间接影响， 神经元的完整性。为了更好地处理可能 作为肠道炎症的基础，并影响这些小鼠中AD相关神经病理学的发展，我们 发起了与巴克的丹·维纳博士的合作，他是适应性免疫系统在免疫系统中作用的专家。 控制代谢组织炎症。进行了细菌分析，并显示了在 AD小鼠结肠中促炎细菌的水平，与AD小鼠结肠中促炎细菌水平的显著富集相一致。 CD 4 +Tbet+（Th 1）免疫细胞群的减少与肠道屏障功能降低和生态失调有关。 作为资助的父母补助金的一部分的其他研究表明，UA喂养的3xAD小鼠显示出显著的 减少神经病变和改善行为缺陷。正如最初的拨款所假设的那样， 这可能部分是由于对CNS中神经元细胞的直接作用。然而，它也可能涉及 这意味着化合物维持肠道完整性和功能并减少肠道炎症的能力。这样做的目的 补充是为我们提供资金，使我们能够确定是否UA的神经保护作用是由于 部分原因在于它能够影响肠道健康。

PROJECT SUMMARY/ABSTRACT The parent award proposes to assess the potential neuroprotective effects of the gut metabolite urolithin A (UA) in the 3xAD Tg model of Alzheimer’s disease (AD). Aim 3 of the grant centers on the hypothesis that reductions in age-related gut microbiota involved in the production of UA from its dietary precursor ellagic acid may contribute to increased neuropathology associated with the 3xAD model and can be prevented by restoration of a more youthful microbiome. In addition to its direct impact on neurons (the subject of the parent grant), UA potentially may also have indirect effects via its ability to maintain gut integrity and function which can have ‘knock on’ effects on neuronal integrity via the gut-brain axis. In order to get a better handle on potential mechanisms that may underlie gut inflammation and influence the development of AD-related neuropathology in these mice, we initiated a collaboration with Dr. Dan Winer at the Buck, an expert on the role of the adaptive immune system in controlling metabolic tissue inflammation. Bacterial profiling was performed and revealed a clear difference in the levels of pro-inflammatory bacteria in the AD mouse colon, coinciding with a striking enrichment in the level of CD4+Tbet+ (Th1) immune cell populations previously linked to reduced gut barrier function and dysbiosis. Additional studies as part of the funded parent grant demonstrated that UA-fed 3xAD mice show significant reductions in Aß neuropathology and improvement in behavioral deficits. As postulated in the original grant, this may be in part due to direct effects on neuronal cells in the CNS. However, it may also involve the compound’s ability to maintain gut integrity and function and reduce gut inflammation. The purpose of this supplement is to provide us with funds to allow us to determine whether UA’s neuroprotective effects are due in part to its ability to influence gut health.