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

载脂蛋白ε4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携带者会发展成血管和新陈代谢 在β-淀粉样蛋白(Aβ)和神经原纤维tau缠结聚集之前几十年的缺陷。 新的证据表明，肠道微生物区系在决定大脑功能方面起着关键作用。 代谢和血管完整性，以及肠道微生物群平衡的变化有可能 在AD的发病机制中起着重要作用。这项研究的基本原理是确定饮食是否 干预措施可以用来改变肠道微生物的组成和活性，这将 从而保护脑血管和代谢功能，减少神经炎症和 类似广告的病理学。一种含有益生素的膳食补充剂将被使用：菊粉，一种非 可消化碳水化合物纤维在胃肠道中发酵，增加益处 微生物区系和喂养通过5个家族性AD突变和过度表达人类Aβ的小鼠 表达人载脂蛋白4(E4FAD)。核心假设是菊粉对大脑有保护作用。 通过对肠道微生物群的调节发挥作用。这一假说将通过追求 以下三个具体目标：1)确定菊粉对肠道微生物群的影响 代谢的多组学研究：2)评价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 分子分析。该项目具有创新性，因为它采用了新颖的、多学科的方法 方法侧重于早期干预，这可能成为预防AD的有效途径。 APOE4携带者通过脑-肠轴诱发痴呆。该项目还具有创新性，因为 它挑战了当前的范式，因为它与AD的治疗有关。而不是移除β或tau 在它们出现后或在认知衰退开始之后，焦点将转移到早期 干预措施可能成为降低AD引起的痴呆症风险的有效方式， 尤其是通过肠道微生物群的调节。该项目将产生巨大的积极影响 因为它们将在APOE的背景下增强对大脑-肠道相互作用的理解 基因分型。此外，微生物组分析和神经成像可用于人类，以及 菊粉相关的饮食在商业上是可用的；因此，这种方法具有很高的转化率 价值。这项研究的结果将为未来的临床试验提供有价值的信息 降低认知正常载脂蛋白4携带者AD风险的益生素饮食。

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.