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/文摘