The intersection of GLP-1, gut microbiota, and brain connectivity in prodromal Alzheimer’s disease

项目总结： 阿尔茨海默病(AD)的早期识别对于预防或延缓疾病的发病至关重要。的确有 目前尚无有效的治疗AD的方法，这可能是多种潜在原因造成的。安装 有证据支持这样一种观点，即阿尔茨海默病在一定程度上是一种具有一系列代谢紊乱的代谢状况 在疾病的早期，甚至在典型的前驱阶段，即遗忘性轻度认知障碍(AMCI)。 动物模型表明，胃肠和神经肽类胰高血糖素样肽-1(GLP-1)是一种很有前途的连接 阿尔茨海默病的肠道-脑轴，尽管这一外周-中枢通路在AD中尚未被定义。我们提出了一个 前驱AD新的Gut-GLP-1相互作用体。我们假设肠道特定的细菌菌株会影响 GLP-1水平并产生影响aMCI患者脑连接模式的小代谢物。 我们将在两个具体目标上检验这一科学前提。在目标1中，我们将确定 急性心肌梗死患者与年龄匹配对照组的GLP-1水平和默认模式网络(DMN)连接模式的比较 一群人。我们将采用严格的方法学设计来测量餐前和餐后GLP-1的水平 并使用尖端的功能磁共振方法评估DMN连接模式。在目标2中，我们寻求 确定aMCI和对照中与DMN连接模式相关的细菌菌株和代谢物 组。我们将对同一时间从同一时间收集的粪便样本进行元基因组测序 Aim1中评估的个人。我们将确定有可能影响GLP-1水平的细菌基因。新陈代谢 标记将与DMN连接模式相关联。总而言之，这些目标将阐明细菌 前驱AD疾病状态中的代谢生物标记物可以对GLP-1水平或活性产生负面影响 影响大脑功能。我们将使用这里收集的数据来启动一项纵向研究，以遵循 代谢和神经成像数据以及已知的AD病理生物标记物如β-受体的研究进展 淀粉样蛋白和tau。我们的目标是确定特定的细菌菌株及其代谢特性， 从正常认知老化到aMCI再到AD的过渡。

Project Summary: Early identification of Alzheimer's disease (AD) is essential for preventing or delaying disease onset. There is currently no effective treatment for AD, which may be attributable to multiple underlying causes. Mounting evidence supports the notion that AD is, in part, a metabolic condition with an array of metabolic perturbations early in the disease, even at the prototypical prodromal stage, i.e. amnestic mild cognitive impairment (aMCI). Animal models indicate that gut- and neuropeptide Glucagon like peptide-1 (GLP-1) is a promising link within the gut-brain axis of AD, although this peripheral-central pathway has yet to be defined in AD. We propose a novel gut-GLP-1 interactome of prodromal AD. We hypothesize that gut specific bacterial strains will influence GLP-1 levels and produce small metabolites that influence brain connectivity patterns in patients with aMCI. We will test this scientific premise in two Specific Aims. In Aim 1, we will determine the relationship between GLP-1 levels and default mode network (DMN) connectivity patterns in aMCI compared to age-matched control cohorts. We will apply rigorous methodological design to measure pre- and post- meal testing GLP-1 levels and assess DMN connectivity patterns using a cutting-edge functional MRI method. In Aim 2, we seek to determine bacterial strains and metabolites associated with DMN connectivity patterns in aMCI and control groups. We will conduct metagenomic sequencing on stool samples collected at similar times from the same individuals assessed in Aim1. We will identify bacterial genes with potential to impact GLP-1 levels. Metabolic markers will be correlated with DMN connectivity patterns. Together, these Aims will elucidate bacterial metabolic biomarkers in a prodromal AD disease state that can negatively affect GLP-1 levels or activity to affect brain functioning. We will use the data collected here to initiate a longitudinal study to follow the progression of metabolic and neuroimaging data along with known AD pathologic biomarkers such as beta- amyloid and tau. Our goal is to determine the specific bacterial strains and their metabolic properties that drive the transition from normal cognitive aging to aMCI to AD.