Supplement to Prebiotics Intervention to Reduce Alzheimer's Disease Risk via Brain-Gut Axis in an APOE4 Mouse Model

在 APOE4 小鼠模型中补充益生元干预以通过脑肠轴降低阿尔茨海默病风险

• 批准号: 10621074
• 负责人: Ai-Ling Lin
• 金额: $ 243.59万
• 依托单位: UNIVERSITY OF MISSOURI-COLUMBIA
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-05-01 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10621074
• 关键词: Supplement; Prebiotics; Intervention; Reduce; Alzheimer

Apolipoprotein ε4 (APOE4) allele is the strongest genetic risk factor for Alzheimer’s disease (AD). It has been shown that cognitively normal APOE4 carriers develop vascular and metabolic deficits decades before the aggregation of beta-amyloid (Aβ) and neurofibrillary tau tangles. Emerging evidence shows that the gut microbiota plays a critical role in determining brain metabolic and vascular integrity, and changes in gut microbiome balance have the potential to contribute greatly to AD pathogenesis. The rationale of the study is to determine if dietary interventions can be used to modify gut microbial composition and activity, which will consequently protect brain vascular and metabolic functions, and reduce neuroinflammation and AD-like pathology. a dietary supplement containing prebiotic will be used: Inulin, a non- digestible carbohydrate fiber fermented in the gastrointestinal tract to increase beneficial microbiota and feed the mice that that overexpresses human Aβ via 5 familial-AD mutations and expresses human APOE4 (E4FAD). The central hypothesis is that Inulin is protective of brain functions via the modulation of gut microbiome. The hypothesis will be tested by pursuing the following three Specific Aims: 1) Identify Inulin’s effects on gut microbiome and associated metabolism using multi-omics; 2) Assess inulin’s effects on brain vascular and metabolic functions through neuroimaging; 3) Determine Inulin’s effects on neuroinflammation using molecular assays. The project is innovative because it employs novel and multidisciplinary methods to focus on early interventions that may become an effective way to prevent AD- induced dementia for APOE4 carriers via brain-gut axis. The project is also innovative because it challenges the current paradigm as it pertains to AD treatment. Instead of removing Aβ or tau after they appear or after the onset of cognitive decline, the focus will be shifted to early interventions that may become an effective way to reduce risk for AD-induced dementia, especially through gut microbiome modulation. The project will have tremendous positive impact as they will enhance the understanding of brain-gut interactions in the context of APOE genotypes. In addition, microbiome analysis and neuroimaging are available for humans, and Inulin-related diets are commercially available; therefore, this approach has high translational value. Outcomes from the study will provide valuable information for future clinical trials with prebiotic diet to reduce AD risk for cognitively normal APOE4 carriers.

载脂蛋白ε 4（APOE4）等位基因是阿尔茨海默病最强的遗传危险因素 （AD）。已经表明，认知正常的APOE4携带者发展血管和代谢异常， 在β-淀粉样蛋白（A β）和神经元tau缠结聚集之前数十年， 新出现的证据表明，肠道微生物群在决定大脑功能方面起着关键作用。 代谢和血管完整性，以及肠道微生物组平衡的变化有可能 在AD发病机制中起重要作用。这项研究的基本原理是确定饮食是否 干预措施可用于改变肠道微生物组成和活性， 从而保护脑血管和代谢功能，减少神经炎症， AD样病理学将使用含有益生元的膳食补充剂：菊粉，一种非- 可消化的碳水化合物纤维在胃肠道发酵，以增加有益的 通过5种家族性AD突变过度表达人A β的小鼠， 表达人APOE4（E4FAD）。核心假设是菊粉对大脑有保护作用 通过调节肠道微生物组发挥作用。该假设将通过追踪 以下三个具体目标：1）确定菊粉对肠道微生物组和相关的影响 2）评估菊粉对脑血管和代谢的影响 通过神经成像功能; 3）确定菊粉对神经炎症的影响， 分子检测该项目是创新的，因为它采用了新颖的和多学科的 注重早期干预的方法可能成为预防AD的有效方法， 通过脑-肠轴诱导APOE4携带者痴呆。该项目也是创新的，因为 它挑战了当前与AD治疗相关的范式。而不是去除A β或tau 在他们出现或认知能力下降后，重点将转移到早期， 干预措施可能成为降低AD诱发痴呆风险的有效方法， 特别是通过肠道微生物组调节。该项目将产生巨大的积极影响 因为它们将增强对APOE背景下脑-肠相互作用的理解 基因型此外，微生物组分析和神经成像可用于人类， 菊粉相关的饮食是市售的;因此，这种方法具有高转化率。 值该研究的结果将为未来的临床试验提供有价值的信息， 益生元饮食，以降低认知正常的APOE4携带者的AD风险。