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.

项目概要/摘要 我们的人口正在老龄化，阿尔茨海默病（AD）的发病率也随之增加。 与年龄相关的疾病不断增加，导致医疗费用增加。 当前与年龄相关的食物增加的原因是美国饮食的摄入量不断增加 添加糖的负面影响部分是由于晚期糖化造成的。 终产物 (AGE) 由糖分子附着的糖化过程形成 没有酶调节的蛋白质或脂质，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，它们可能会致病，因为 AGE 会促进氧化 压力和炎症是 AD 增加的第三个因素。 研究已将年龄相关疾病与微生物组的变化联系起来。 该提案的假设是，食用含糖饮食会改变微生物组， 我们将通过两个具体目标来解决这一假设。 使用秀丽隐杆线虫-大肠杆菌系统。 我们的实验性大肠杆菌范例是这些研究的优秀系统。 因为：（1）线虫是食菌动物，并且与细菌有必然的共生关系。 (2) 线虫拥有 （3）遗传工具是进化上保守的应激和免疫信号通路； 可用的包括 AD 转基因菌株，其中人类 β-淀粉样蛋白前体蛋白 (Aβ (4)我们可以改变环境（加糖） 导致饮食中 AGEs(dAGEs) 水平的变化；以及 (5) 我们的初步数据显示 当线虫食用活的（微生物群）或热灭活的（无微生物群）高糖含量的线虫时 dAGE 大肠杆菌、线虫的寿命和健康寿命也会缩短。 在具体目标 1 中，我们将证明微生物群作为压力缓冲的重要性。 解决含糖高 dAGEs 饮食对热致死 AD 转基因动物的影响 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）提供了机制见解。该提案利用了一种共生关系。 定义含糖量/高 dAGEs 饮食如何促进 Aβ 积累。 一年期间可能会改变我们对添加膳食葡萄糖影响的理解 长期目标是改变饮食以延缓甚至消除 AD 的发作。