Dissecting connections between diet, the microbiome and Alzheimers disease

剖析饮食、微生物组和阿尔茨海默病之间的联系

• 批准号: 10740056
• 负责人: HEIDI A TISSENBAUM
• 金额: $ 25.13万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-15 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10740056
• 关键词: Address; Advanced Glycosylation End Products; Affect; Age; Aging; Alzheimer' s Disease; Alzheimer' s disease patient; American; American diet; Amino Acids; Amyloid beta-42; Amyloid beta-Protein; Amyloid beta-Protein Precursor; Animal Diseases; Animals; Bacteria; Brain; Buffers; Caenorhabditis elegans; Circulation; Consumption; Data; Diabetes Mellitus; Diet; Dietary Sugars; Economics; Environment; Escherichia coli; Food; Genes; Genetic; Glucose; Goals; Grant; Health; Health Care Costs; Human; Immune; Immune signaling; Incidence; Inflammation; Intervention; Link; Lipids; Longevity; Metabolism; Microbe; Movement; Muscle; Neurons; Orthologous Gene; Oxidative Stress; Paralysed; Pathogenicity; Pathway interactions; Peptides; Persons; Population; Process; Proteins; Publishing; Regulation; Series; Severities; Signal Pathway; Silver; Source; Stress; Structure; System; Testing; Tissues; Transgenic Animals; Transgenic Organisms; Tsunami; abeta accumulation; constitutive expression; dietary; gastrointestinal system; glycation; gut microbiota; healthspan; inducible gene expression; insight; microbiome; microbiome alteration; microbiota; mutant; presenilin; promoter; social stress; stress management; sugar; tool

Project Summary/Abstract Our population is aging. As our population ages, the incidence of Alzheimer’s Disease (AD), an age-associated illness, grows, resulting in elevated health care costs. A second factor contributing to the current rise in age-associated aliments is the American diet with its ever-increasing amount of added sugar. The negative effects of added dietary sugar is in part due to advanced glycation end products (AGEs) which form from the process of glycation where a sugar molecule attaches to a protein or lipid without enzymatic regulation thereby altering its structure and/or function. AGEs form in normal metabolism but when AGEs rise to high levels in tissues and circulation, as in diabetes or high dietary sugar, they can become pathogenic since AGEs promote oxidative stress and inflammation. A third contributor to the increases in AD is the microbiome; recent studies have linked age-associated illness with changes in the microbiome. The central unifying hypothesis of this proposal is that consumption of a sugar-loaded diet alters the microbiome and contributes to the onset and severity of AD. We will address this hypothesis with two specific aims using a Caenorhabditis elegans–Escherichia coli system. Our experimental C. elegans–E. coli paradigm is an excellent system for these studies because: (1) C. elegans are bacterivores and have an obligatory symbiotic relationship with microbes as their food source, which becomes the intestinal microbiota; (2) C. elegans possess stress and immune signaling pathways that are evolutionarily conserved; (3) Genetic tools are available including transgenic strains for AD whereby human β-Amyloid precursor protein (Aβ peptide) is driven by a tissue specific promoter. (4) We can modify the environment (added sugar) resulting in changes in the levels of dietary AGEs(dAGEs); and (5) Our preliminary data show when C. elegans consume live (microbiota) or heat killed (no microbiota) sugar-loaded high- dAGE E. coli, C. elegans have a shortened lifespan and reduced healthspan. Our results also demonstrate the importance of the microbiota as a buffer for stress. In Specific Aim 1, we will address the effects of a sugar-loaded high-dAGEs diet on AD transgenic animals with heat killed or live bacteria. In Specific Aim 2, we use a series of genetic tools, (including mutants, transgenics)to provide mechanistic insight. This proposal exploits a symbiotic relationship to define how a sugar loaded/high dAGEs diet promotes Aβ accumulation. Our results in the two- year period could be paradigm shifting in our understanding of the impact of added dietary glucose on AD. The long-term goal is to modify diet to delay or even eliminate the onset of AD.

项目总结/摘要 我们的人口正在老龄化。随着我们人口的老龄化，阿尔茨海默病（AD）的发病率， 与年龄相关的疾病，增长，导致医疗保健成本上升。第二个因素是 与年龄相关的食物的增加是美国饮食的不断增加 添加糖。饮食中添加糖的负面影响部分是由于晚期糖基化 终产物（AGEs），由糖分子附着的糖基化过程形成 与蛋白质或脂质结合而不受酶调节，从而改变其结构和/或功能。 AGEs在正常代谢中形成，但当AGEs在组织和循环中升高到高水平时， 在糖尿病或高糖饮食中，由于AGEs促进氧化， 压力和炎症。AD增加的第三个因素是微生物组;最近 研究将年龄相关疾病与微生物组的变化联系起来。中央统一 该建议的假设是，含糖饮食的消耗改变了微生物组， 有助于AD的发作和严重程度。我们将以两个具体目标来论述这一假设 使用秀丽隐杆线虫-大肠杆菌系统。 我们的实验C. elegans-E. coli paradigm是一个很好的研究系统 因为：（1）C.秀丽线虫是食菌动物，与 微生物作为它们的食物来源，这成为肠道微生物群;（2）C.优雅的人拥有 应激和免疫信号通路是进化上保守的;（3）遗传工具， 包括AD的转基因菌株，其中人β-淀粉样前体蛋白（Aβ 肽）由组织特异性启动子驱动。(4)我们可以改变环境（添加糖） 导致饮食AGEs（dAGEs）水平的变化;（5）我们的初步数据显示， 当C.秀丽线虫消耗活的（微生物群）或热杀死的（无微生物群）高糖- dAGE E. coli、C.秀丽线虫的寿命缩短，健康寿命缩短。我们的研究结果还 证明了微生物群作为压力缓冲器的重要性。具体目标1： 解决了含糖高dAGEs饮食对AD转基因动物的影响， 或活细菌。在《特定目标2》中，我们使用了一系列遗传工具，（包括突变体， 转基因学）以提供机械的洞察力。这一提议利用了一种共生关系， 定义含糖/高dAGEs饮食如何促进Aβ积累。我们的结果是- 一年的时间可能是我们对添加膳食葡萄糖影响的理解的范式转变 在AD。长期目标是改变饮食以延迟甚至消除AD的发作。