Environmental factors in pathobiology of dementia: the role of PCB exposure, microbiome, and tissue barrier dysfunction

痴呆病理学中的环境因素：PCB 暴露、微生物组和组织屏障功能障碍的作用

• 批准号: 10558120
• 负责人: HANS-JOACHIM LEHMLER
• 金额: $ 74.64万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-01-01 至 2025-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10558120
• 关键词: APP-PS1; Acceleration; Adverse effects; Affect; Alzheimer' s Disease; Alzheimer' s disease related dementia; Alzheimer' s disease risk; Attenuated; Bile Acids; Blood - brain barrier anatomy; Blood Vessels; Blood brain barrier dysfunction; Brain; Cause of Death; Cognition Disorders; Complex; Control Animal; Data; Dementia; Development; Diagnosis; Disease; Dose; Elderly; Ensure; Environmental Exposure; Environmental Health; Environmental Risk Factor; Etiology; Experimental Models; Exposure to; FAIR principles; Family member; Female; Functional disorder; Goals; Health; Healthcare; Homeostasis; Human; Inflammatory Response; Intestines; Iowa; Knowledge; Lead; Longevity; Measures; Mediating; Mediation; Memory Loss; Metabolism; Mission; Modeling; Mus; Neurodegenerative Disorders; Neurodevelopmental Disorder; Neurotoxins; Organism; Outcome; Pathologic; Pathology; Persons; Phenotype; Polychlorinated Biphenyls; Proteins; Public Health; Quality of life; Research; Ribosomal RNA; Role; Senile Plaques; Serum; Severities; Systems Biology; Testing; Tight Junctions; Time; Tissues; Toxic Environmental Substances; Toxic effect; United States; United States National Institutes of Health; Universities; Vascular Diseases; bile acid metabolism; blood-brain barrier function; comparison control; data reuse; epidemiology study; genetic risk factor; gut bacteria; gut microbiome; human disease; in vivo; insight; intestinal barrier; male; microbiome; microbiome composition; mouse model; neurotoxic; object recognition; pre-clinical; premature; prevent; programs; tau-1; translational study

PROJECT SUMMARY/ABSTRACT Alzheimer’s Disease (AD) is the most common cause of dementia in the elderly, and it is the sixth leading cause of death in the United States. AD currently cannot be prevented, cured, or even slowed, and it has a significant public health impact in terms of health care dollars and quality of life for those affected and their family members. Experimental models of ADRD have implicated the gut microbiome-bile acid-brain axis in the development and progression of ADRD. Neurotoxic environmental toxicants, such as polychlorinated biphenyls (PCBs), alter the function of the microbiome, resulting in an altered bile acid homeostasis; however, it is unknown if PCB-mediated changes in the gut microbiome-bile acid-brain axis play a role in the etiology of ADRD. Furthermore, epidemiological studies have major limitations assessing the complex effects of PCB exposure on the gut microbiome-bile acid-brain axis across the lifespan. Thus, there is a critical need to assess how human-relevant PCB mixtures alter the development and progression of ADRD-like phenotypes in experimental models of ADRD via the gut microbiome-bile acid-brain axis. The long-term goal of the transdisciplinary team assembled for this project is to characterize how environmental exposures contribute to ADRD and ultimately prevent ADRD through a precision environmental health paradigm. The translational objective is to demonstrate with a systems biology approach that exposure to a human-relevant PCBs mixture contributes to and accelerates the etiology of ADRD-type outcomes in vivo. The central hypothesis is that exposure to PCBs adversely affects the ADRD phenotype in rTg4510 and APP/PS1 mice, two experimental models of ADRD, by causing microbiome-mediated alterations in the bile acid homeostasis and affecting vascular function in a dose and exposure time-dependent manner. This hypothesis integrates strong preliminary data from the research team showing that PCBs are present in the human brain, affect the microbiome, alter bile acid homeostasis, and cause vascular dysfunction. The hypothesis will be tested using a systems biology approach by assessing how exposure to a human-relevant PCB mixture affects ADRD-related outcomes in experimental models of ADRD. The Specific Aims are to a) characterize effects of PCB exposure on gut microbiome composition and circulating bile acids; b) study the effects of PCB exposure on vascular function, and c) identify ADRD-type pathological changes and memory loss in the brain of PCB exposed rTg4510 or APP/PS1 mice. To ensure integration across all Aims, mediation analysis will be used to demonstrate that the microbiome and/or vascular dysfunction mediates the effects of PCBs on ADRD-type outcomes. These studies will demonstrate that PCB exposure leads to accelerated progression and more severe disease pathology in experimental ADRD models. Identifying PCBs as environmental risk factors that alter ADRD-related outcomes will lay the groundwork for mechanistic studies and inform translational studies for preventing ADRD mediated by environmental toxicants using a precision environmental health paradigm.

项目摘要/摘要 阿尔茨海默氏病（AD）是老年痴呆症最常见的原因，这是第六个主要原因 在美国死亡。当前的广告无法预防，治愈甚至放慢速度，并且具有重要意义 公共卫生对受影响者及其家人的医疗保健收入和生活质量的影响。 ADRD的实验模型已在发育和 Adrd的进展。神经毒性环境有毒物质，例如多氯联苯（PCB），改变了 微生物组的功能，导致胆汁酸稳态改变；但是，未知PCB介导的 肠道微生物 - 波兰酸 - 脑轴的变化在ADRD的病因中起作用。此外， 流行病学研究具有重大局限性，评估了PCB暴露对肠道的复杂作用 整个寿命的微生物组硼酸 - 脑轴轴。这是迫切需要评估与人类与人类有关的 PCB混合物在实验模型中改变了ADRD样表型的发展和进展 通过肠道微生物组裂酸脑轴ADRD。跨学科团队的长期目标是组装 因为这个项目是要表征环境暴露是如何对ADRD贡献的，并最终阻止了ADRD 通过精确的环境健康范式。翻译的目标是通过系统演示 暴露于与人与人与PCB的混合物的生物学方法有助于病因并加速病因 体内的Adrd型结果。中心假设是暴露于PCB会对ADRD产生不利影响 RTG4510和APP/PS1小鼠中的表型，两种ADRD的实验模型，通过引起微生物组介导 胆汁酸稳态的改变，并影响剂量和暴露时间的血管功能 方式。该假设整合了研究团队的强大初步数据，表明PCB是 存在于人脑中，会影响微生物组，改变胆汁酸稳态并引起血管功能障碍。 该假设将通过系统生物学方法进行测试，通过评估如何暴露于人类与人类有关 PCB混合物会影响ADRD实验模型中与ADRD相关的结果。具体目标是A） PCB暴露对肠道微生物组组成和循环胆汁酸的影响； b）研究 PCB暴露对血管功能的影响，c）确定ADRD型病理变化和记忆丧失 在PCB暴露的RTG4510或APP/PS1小鼠的大脑中。为了确保所有目标的集成，调解分析 将用于证明微生物组和/或血管功能障碍介导了PCB对 ADRD类型的结果。这些研究将表明，PCB暴露会导致加速进展和 实验性ADRD模型中更严重的疾病病理学。将PCB识别为环境风险因素 这种改变与ADRD相关的结果将为机械研究奠定基础，并为翻译研究提供信息 用于防止使用精确环境健康范式介导的环境有毒物质介导的ADRD。