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.

项目概要/摘要 家长奖提议评估肠道代谢物尿石素 A 的潜在神经保护作用 (UA) 在阿尔茨海默病 (AD) 的 3xAD Tg 模型中的作用 资助的目标 3 的中心假设是： 与年龄相关的肠道微生物群减少，这些微生物群参与从膳食前体鞣花酸中产生 UA 可能会导致与 3xAD 模型相关的神经病理学增加，并且可以通过以下方式预防 恢复更年轻的微生物组。 除了对神经元的直接影响（家长资助的主题）之外，UA 还可能具有 通过维持肠道完整性和功能的能力产生间接影响，这可以对 通过肠脑轴的神经完整性，以便更好地处理可能的潜在机制。 肠道炎症的基础并影响这些小鼠 AD 相关神经病理学的发展，我们 与巴克大学的 Dan Winer 博士发起了合作，Dan Winer 博士是适应性免疫系统在疾病中的作用方面的专家。 控制代谢组织炎症进行了细菌分析并揭示了明显的差异。 AD 小鼠结肠中促炎细菌的水平，与该水平的显着富集相一致 CD4+Tbet+ (Th1) 免疫细胞群先前与肠道屏障功能降低和生态失调有关。 作为资助的家长资助的一部分的其他研究表明，UA 喂养的 3xAD 小鼠表现出显着的 正如最初拨款中所假设的，Aß 神经病理学的减少和行为缺陷的改善。 这可能部分是由于对中枢神经系统神经细胞的直接影响，但也可能涉及到。 化合物维持肠道完整性和功能并减少肠道炎症的能力。 补充是为了给我们提供资金，让我们能够确定UA的神经保护作用是否应有 部分原因在于它影响肠道健康的能力。