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; 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 父母奖的提案，以评估肠道代谢物尿石素A的潜在神经保护作用 （UA）在阿尔茨海默氏病（AD）的3XAD TG模型中。授予中心的目标3关于以下假设 与年龄相关的肠道菌群的减少参与UA产生的饮食前体胆酸产生 可能有助于增加与3XAD模型相关的神经病理学，并且可以通过 恢复更年轻的微生物组。 除了对神经元的直接影响（父母赠款的主题）外，UA还可能有 通过维持肠道完整性和功能的能力间接影响，这可以“敲击”对 通过肠脑轴神经元完整性。为了更好地处理可能的潜在机制 肠道注射并影响这些小鼠中与广告相关的神经病理学的发展，我们 与Dan Winer博士在Buck的合作中启动，该专家是适应性免疫系统在 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，与该水平的罢工富集一致 CD4+ TBET+（TH1）的免疫细胞群体先前与肠道屏障功能降低和营养不良有关。 作为资助的父母赠款的一部分的其他研究表明，UA喂养的3XAD小鼠显示出显着的 Aß神经病理学的减少和行为定义的改善。如原始赠款中发布的 这可能部分是由于对中枢神经系统中神经元细胞的直接影响。但是，它也可能涉及 化合物保持肠道完整性和功能并减少肠道注射的能力。这个目的 补充是为我们提供资金，以允许我们确定UA的神经保护作用是否应到期 部分影响其影响肠道健康的能力。