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.

项目总结/摘要 阿尔茨海默氏病（AD）是老年痴呆症最常见的原因，并且是第六大原因 死亡在美国。AD目前无法预防、治愈，甚至无法减缓，并且它具有显著的 在卫生保健费用和受影响者及其家庭成员的生活质量方面对公共卫生的影响。 ADRD的实验模型表明肠道微生物组-胆汁酸-脑轴参与了ADRD的发展， ADRD的进展。神经毒性的环境毒物，如多氯联苯（PCB），改变 微生物组的功能，导致胆汁酸稳态改变;然而，尚不清楚PCB介导的 肠道微生物组-胆汁酸-脑轴的变化在ADRD的病因学中起作用。此外，委员会认为， 流行病学研究在评估多氯联苯暴露对肠道的复杂影响方面存在重大局限性 微生物组-胆汁酸-大脑轴。因此，迫切需要评估与人类相关的 PCB混合物改变ADRD样表型在实验模型中的发展和进展 ADRD通过肠道微生物组-胆汁酸-脑轴。跨学科团队的长期目标是 本项目的目的是描述环境暴露如何导致ADRD并最终预防ADRD 通过一个精确的环境健康范例。翻译的目标是用一个系统来演示 生物学方法，暴露于人类相关的多氯联苯混合物有助于并加速病因学 ADRD类型的结果。核心假设是，接触多氯联苯会对ADRD产生不利影响 在rTg 4510和APP/PS1小鼠（两种ADRD实验模型）中，通过引起微生物群介导的 胆汁酸体内平衡的改变，并以剂量和暴露时间依赖性影响血管功能 方式这一假设整合了来自研究小组的强有力的初步数据，这些数据表明，多氯联苯是 存在于人脑中，影响微生物组，改变胆汁酸体内平衡，并导致血管功能障碍。 该假设将使用系统生物学方法进行测试，评估如何暴露于人类相关的 多氯联苯混合物影响ADRD实验模型中的ADRD相关结果具体目标是a） 表征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，以及c）识别ADRD型病理变化和记忆丧失 在PCB暴露的rTg 4510或APP/PS1小鼠的脑中。为了确保所有目标的集成， 将用于证明微生物组和/或血管功能障碍介导多氯联苯对 ADRD类型结局。这些研究将证明，接触多氯联苯会加速疾病进展， 在实验性ADRD模型中更严重的疾病病理学。确定多氯联苯为环境风险因素 改变ADRD相关结果的研究将为机制研究奠定基础，并为转化研究提供信息。 使用精确的环境健康范例预防由环境毒物介导的ADRD。