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.

项目摘要/摘要 我们的人口正在衰老。随着我们人口的年龄，阿尔茨海默氏病（AD）的事件 与年龄相关的疾病，增长，导致医疗保健费用升高。第二个因素促成 与年龄相关的息肉目前的增长是美国饮食的增长量不断增加 添加糖。添加饮食糖的负面影响部分是由于晚期糖化 糖分子附着的糖化过程形成的最终产品（年龄） 在没有酶调节的情况下进行蛋白质或脂质，从而改变其结构和/或功能。 在正常代谢中形成年龄，但是当年龄在组织和循环中升高到高水平时， 在糖尿病或高饮食糖中，由于年龄促进氧化性，它们可能会变得致病 压力和炎症。 AD增加的第三个贡献者是微生物组。最近的 研究将与年龄相关的疾病与微生物组的变化联系起来。中央统一 该提议的假设是消耗糖饮食会改变微生物组和 有助于AD的发作和严重性。我们将以两个具体的目的解决这一假设 使用秀丽隐杆线虫 - 埃塞里希菌系统系统。 我们的实验性秀丽隐杆线虫–e。大肠杆菌范式是这些研究的绝佳系统 因为：（1）秀丽隐杆线虫是细菌，与 微生物作为食物来源，成为肠道菌群； （2）秀丽隐杆线虫拥有 应力和免疫信号通路在进化上保守； （3）遗传工具是 可用的AD转基因菌株，其中人β-淀粉样蛋白前体蛋白（Aβ） 肽）由组织特异性启动子驱动。 （4）我们可以修改环境（添加糖） 导致饮食年龄水平的变化（DAGE）； （5）我们的初步数据显示 当秀丽隐杆线虫在摄入（微生物群）或杀死的热量（无菌群）时摄 Dage E. Coli，C。秀丽隐杆线虫的寿命缩短和降低的HealthSpan。我们的结果也是如此 证明微生物群作为应力缓冲液的重要性。在特定目标1中，我们将 解决糖加饮食对广告转基因动物的影响，并杀死热量 或活细菌。在特定目标2中，我们使用一系列遗传工具（包括突变体， 转基因）提供机械洞察力。该建议利用了与 定义糖负荷/高高饮食如何促进Aβ的积累。我们的结果在两个 在我们对添加饮食葡萄糖的影响的理解时，年度可能是范式转移 在广告上。长期目标是修改饮食以延迟甚至消除AD的发作。