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

项目摘要/摘要 阿尔茨海默病(AD)是导致老年人痴呆的最常见原因，也是第六大主要原因 在美国的死亡。AD目前无法预防、治愈，甚至无法减缓，而且它有显著的 在医疗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群-胆汁酸-脑轴参与了ADRD的发育和 ADRD的进展。神经毒性环境毒物，如多氯联苯(PCBS)，会改变 微生物组的功能，导致胆汁酸稳态改变；然而，是否由多氯联苯介导尚不清楚 肠道微生物群-胆汁酸-脑轴的改变在ADRD的病因中发挥了作用。此外， 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主要局限性 微生物群-胆汁酸-脑轴贯穿整个生命周期。因此，迫切需要评估与人类有多大关系 多氯联苯混合物改变ADRD样表型在实验模型中的发展和进展 ADRD通过肠道微生物群-胆汁酸-脑轴。组建的跨学科团队的长期目标 这个项目的目的是描述环境暴露如何导致ADRD，并最终预防ADRD 通过精确的环境健康范例。翻译的目标是用一个系统来演示 接触与人类相关的多氯联苯混合物有助于并加速病因的生物学方法 体内ADRD类型的结局。中心假设是，接触多氯联苯会对ADRD产生不利影响 微生物组介导的ADRD实验模型rTg4510和APP/PS1小鼠的表型 胆汁酸稳态的改变和对血管功能的影响呈剂量和暴露时间依赖性 举止。这一假说整合了来自研究小组的强有力的初步数据，表明多氯联苯 存在于人类大脑中，影响微生物群，改变胆汁酸平衡，并导致血管功能障碍。 这一假设将使用系统生物学方法进行验证，方法是评估与人类相关的 在ADRD的实验模型中，多氯联苯混合物影响ADRD相关的结果。具体目标是a) 表征接触多氯联苯对肠道微生物群组成和循环胆汁酸的影响；b)研究 接触多氯联苯对血管功能的影响，以及c)识别ADRD型病变和记忆丧失 在多氯联苯暴露的rTg4510或APP/PS1小鼠的脑内。为确保所有目标的整合，调解分析 将被用来证明微生物组和/或血管功能障碍介导了多氯联苯对 ADRD类型的结果。这些研究将证明，接触多氯联苯会加速进展，并 实验性ADRD模型中更严重的疾病病理学。将多氯联苯确定为环境风险因素 这将改变ADRD相关的结果，为机械论研究奠定基础，并为翻译研究提供信息 用于使用精确的环境健康范例预防环境毒物介导的ADRD。

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.