Role of Neuroprotective Indoles in Delaying the Onset of Cognitive Decline

项目摘要/摘要 这一建议的重点是由我们提出的一个新的假设，即年龄相关的年龄变化 由微生物区系产生的某些神经保护分子的水平可以影响疾病的发生和/或发生率 阿尔茨海默病(AD)引起的轻度认知功能下降(MCI)的进展。我们和其他人证明了 与吲哚类物质相关的小分子，来自肠道细菌，通过不同的 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 时间证明，其中一些吲哚对生物系统有几个有益的影响，包括神经保护。 此外，这些物质具有几种对阿尔茨海默病治疗很重要的性质。1)它们是 神经保护；2)它们阻止淀粉样蛋白聚集成有毒形式；3)它们(由其他人显示) 具有抗炎作用。 来自几个独立调查人员的研究证实并扩大了我们的初步发现和 表明细菌衍生的吲哚延长了包括轮虫在内的各种生物的寿命和健康范围， 果蝇、黑腹果蝇和老鼠。有人提出，微生物区系中与年龄相关的变化 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。这个 调节微生物区系对大脑的多种影响的细菌分子的身份还没有完全确定。 例如，在人类中，血清中高水平的吲哚-3-丙酸与发病率的降低密切相关。 2型糖尿病。然而，关于这些水平的现有信息有限 物质和与年龄相关的神经退行性疾病的发病，如MCI和AD。 包括新陈代谢组学在内的大规模图谱技术为相关的新发现打开了大门 年龄相关性神经退行性疾病的发病机制。通过应用代谢组学，我们建议 研究血清中这些小分子的水平是否会影响发病年龄和发病率 阿尔茨海默病所致的MCI进展。在积极研究期间，将在几个时间间隔内采集血清样本 句号。我们的结果将得到补充，并与正常对照、MCI受试者的样本进行比较 (转换者和非转换者)获得了两个AD中心，我们与它们建立了协作 安排好了。使用代谢组学方法和计算机算法，我们将寻找相关的 血清神经保护性吲哚水平与MCI发病率的相互作用及其相互关系 随着时间的推移，认知能力下降和大脑萎缩的速度。 这是一组探索性的项目，旨在为更大的机械研究获得初步数据 和治疗性干预。

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.