Role of Neuroprotective Indoles in Delaying the Onset of Cognitive Decline

项目概要/摘要 这一建议的重点是一个新兴的假设，由我们开发，即年龄相关的变化， 由微生物群产生的某些神经保护分子的水平可以影响神经保护的发生和/或速率。 由于阿尔茨海默病（AD）导致的轻度认知衰退（MCI）的进展。我们和其他人证明， 与吲哚物质相关的小分子，来源于肠道细菌，通过多种途径发挥系统作用。 促进细胞保护和减少炎症的途径。二十多年前，我们首次展示了 同时，这些吲哚中的一些对生物系统有几种有益的作用，包括神经保护。 此外，这些物质具有对AD治疗重要的几种性质。1)他们是 神经保护; 2）它们防止淀粉样蛋白聚集成毒性形式; 3）它们被证明（由其他人） 具有抗炎作用。 来自几个独立研究者的研究证实并扩展了我们的初步发现， 表明细菌衍生的吲哚延长了各种生物的寿命和健康寿命，包括轮虫， 果蝇和老鼠。有人提出，与年龄相关的微生物群变化 导致与年龄相关的虚弱，包括与年龄相关的神经退行性疾病的发展。的 介导微生物群对脑的多种作用的细菌分子的身份还没有完全确定。 例如，在人类中，高血清水平的吲哚-3-丙酸与降低发病率密切相关。 2型糖尿病的症状然而，关于这些物质的水平，现有的资料有限。 物质和年龄相关的神经退行性疾病，如MCI和AD的发病。 包括代谢组学在内的大规模分析技术为以下新发现打开了大门： 与年龄相关的神经退行性疾病的发病机制。通过应用代谢组学，我们建议 研究这些小分子在血清中的水平是否影响发病年龄和发病率， AD导致的MCI进展。在活性研究期间，将在几个时间间隔采集血清样本 期我们的结果将得到补充，并与正常对照组、MCI受试者的样本进行比较 （转换器和非转换器）获得了两个AD中心，我们建立了合作 安排使用代谢组学方法和计算机算法，我们将寻找相关的 血清中神经保护性吲哚水平与MCI发病率之间的相互作用，以及 以及随着时间的推移认知能力下降和脑萎缩的速度。 这是一组探索性的项目，旨在为更大的机理研究获得初步数据 和治疗干预。

PROJECT SUMMARY/ABSTRACT This proposal is focused on an emerging hypothesis, developed by us, that age-related changes in the level of certain neuroprotective molecules, produced by the microbiota, can influence the onset and/or rate of progression of mild cognitive decline (MCI) due to Alzheimer’s disease (AD). We and others demonstrated that small molecules related to indole substances, derived from intestinal bacteria, act systemically through diverse pathways to promote cellular protection and reduce inflammation. Over two decades ago, we showed for the first time, that some of these indoles have several beneficial effects on biological systems, including neuroprotection. In addition, these substances have several properties that are important to AD therapeutics. 1) They are neuroprotective; 2) They prevent the aggregation of amyloid into toxic forms and 3) They were shown (by others) to have anti-inflammatory properties. Studies from several independent investigators have confirmed and expanded our initial findings and showed that bacteria-derived indoles extend lifespan and health-span of diverse organisms, including rotifers, Drosophila melanogaster, and mice. It has been proposed that age-associated shifts in the microbiota contributes to age-related infirmity, including the development of age-related neurodegenerative disease. The identities of the bacterial molecules mediating multiple effects of the microbiota on the brain are not fully defined. In humans, high serum levels of indole-3-propionic acid, for example, were tightly linked to a decreased incidence of diabetes mellitus type 2. However, there is limited information available regarding the levels of these substances and the onset of age-related neurodegenerative disorders such as MCI and AD. Wide-scale profiling technologies, including metabolomics, open the door for novel discoveries related to the pathogenesis of age-related neurodegenerative diseases. By applying metabolomics, we propose to investigate whether the levels of these small molecules in the serum influence the age of onset and rates of progression of MCI due to AD. Serum samples will be obtained at several time intervals during the active study period. Our results will be supplemented and compared with samples from normal controls, subjects with MCI (converters and non-converters) obtained two AD Centers with which we established collaborative arrangements. Using a metabolomics approach and computerized algorithms, we will seek correlative interactions between serum levels of neuroprotective indoles and the incidence of MCI as well as between these and the rate of cognitive decline and brain atrophy, over time. This is an exploratory set of projects, designed to obtain preliminary data for larger mechanistic studies and therapeutic interventions.