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

关于肠道代谢物尿石素 A 如何延长寿命和预防 AD 的新机制见解

• 批准号: 10614896
• 负责人: Julie Kay Andersen
• 金额: $ 46.15万
• 依托单位: BUCK INSTITUTE FOR RESEARCH ON AGING
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-30 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10614896
• 关键词: Adaptive Immune System; Alzheimer' s Disease; Alzheimer' s disease model; Amyloid beta-Protein; Award; Bacteria; Behavioral; Cells; Collaborations; Colon; Development; Ellagic Acid; Funding; Grant; Immune; Inflammation; Inflammatory; Link; Longevity; Maintenance; Metabolic; Modeling; Mus; Nerve Degeneration; Neurons; Parents; Population; Production; Role; Tissues; Wine; age related; dietary; dysbiosis; gut health; gut inflammation; gut microbiota; gut-brain axis; insight; microbiome; neuropathology; parent grant; prevent; restoration

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.

项目摘要/摘要 家长奖建议评估肠道代谢物尿锂素A的潜在神经保护作用 (UA)在3xAD-TG阿尔茨海默病(AD)模型中。赠款的目标3以假设为中心 与年龄相关的肠道微生物群的减少，这些微生物群参与了从其饮食前体鞣花酸中产生尿酸 可能导致与3xAD模型相关的神经病理增加，并可通过以下方法预防 恢复一个更年轻的微生物群。 除了对神经元的直接影响(父母拨款的对象)，尿酸还可能有 通过其维持肠道完整性和功能的能力产生间接影响，从而对 通过肠道-脑轴的神经元完整性。为了更好地掌握可能存在的潜在机制 在这些小鼠中，肠道炎症和影响AD相关神经病理的发展是基础，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 控制代谢组织炎症。进行了细菌分析，显示出明显的差异 AD小鼠结肠中促炎性细菌的水平，与其水平显著升高相吻合 以前与肠道屏障功能降低和生物失调有关的CD4+Tbet+(Th1)免疫细胞群。 作为资助父母基金的一部分，其他研究表明，UA喂养的3xAD小鼠表现出显著的 神经病理的减少和行为缺陷的改善。正如最初的拨款所假设的那样， 这可能部分是由于对中枢神经系统神经细胞的直接影响。但是，它也可能涉及 化合物的能力，以保持肠道完整性和功能，并减少肠道炎症。这样做的目的是 补充是为我们提供资金，使我们能够确定尿酸的神经保护作用是否应有 这在一定程度上是因为它有能力影响肠道健康。