Impact of Ambient Ultrafine Particle Exposures on Alzheimer's Disease Progression

描述（由申请人提供）：阿尔茨海默病（AD）是一种毁灭性的神经退行性疾病，与进行性功能下降和痴呆相关。散发性阿尔茨海默病被认为是遗传易感性和环境因素共同作用的结果。炎症过程被认为是在大脑内启动和/或传播AD相关病理的必要条件，许多环境触发因素与AD风险增加有关。研究计划：我们假设吸入超细颗粒富集的环境空气污染（HUCAPS）气溶胶会加速ad相关病理，并且早期暴露会导致比成年后期更严重的病理。此外，考虑到炎症与ad相关发病机制之间的联系，我们进一步假设一种关键的炎症调节因子，即肿瘤坏死因子(TNF)-a的拮抗作用将减轻暴露相关的病理。我们将使用一种具有良好特征的AD遗传小鼠模型（3xTg-AD）来验证我们的假设，该模型会发展为进行性人类样β -淀粉样蛋白和tau缠结病理。小鼠将暴露于使用独特的固定式浓缩系统（HUCAPS）富集超细颗粒的交通相关气溶胶中。我们将评估遗传背景、发育年龄和暴露后时间对吸入示踪纳米颗粒在中枢神经系统（CNS）、肺和神经炎症过程、ad相关病理的严重程度和进展以及功能性学习和记忆行为的影响。我们的目标将满足以下三个具体目标来验证我们的假设：1)定义暴露于HUCAPS后CNS中示踪颗粒的区域积累和保留的变化作为年龄和AD病理状态的函数；2)确定HUCAPS气溶胶暴露对3xTg-AD小鼠中枢神经系统炎症过程进展、ad相关病理和认知能力下降的年龄相关性影响；3)在中枢或外周TNF阻断3xTg-AD小鼠后，研究TNF在HUCAPS气溶胶诱导的炎症和病理CNS变化中的作用。预期结果：这些合作研究将利用两个实验室的集体专业知识，在颗粒空气污染、肺生物学、神经炎症和AD领域建立研究项目。这些新的研究旨在了解环境空气污染暴露如何影响脑神经炎症过程和阿尔茨海默病的发病机制，从而更好地理解环境暴露在正常衰老和慢性神经退行性疾病中的影响。这些发现将对公共卫生政策产生深远的影响，并将使人们能够开发针对这种使人衰弱且代价高昂的疾病的治疗干预措施。

DESCRIPTION (provided by applicant): Alzheimer's disease (AD) is a devastating neurodegenerative disorder associated with progressive functional decline and dementia. Sporadic AD cases are believed to arise from a combination of genetic susceptibility and environmental factors. Inflammatory processes are thought to be integral for initiating and/or propagating AD-associated pathology within the brain and a number of environmental triggers are associated with increased AD risk. Research Plan: We hypothesize that inhalation exposures to ultrafine particle-enriched ambient air pollution (HUCAPS) aerosols will accelerate AD-associated pathology and that early life exposures will lead to more severe pathology than exposures that occur in late adulthood. Moreover, given the link between inflammation and AD-related pathogenesis, we further hypothesize that antagonism of a key inflammatory regulator, namely tumor necrosis factor (TNF)-a, will lessen exposure-related pathology. We will test our hypothesis using a well-characterized genetic mouse model of AD (3xTg-AD) that develops progressive human-like beta-amyloid and tau tangle pathology. Mice will be exposed to traffic-related aerosols that have been enriched for ultrafine particles using a unique stationary concentrator system (HUCAPS). We will evaluate the impact of genetic background, developmental age, and post-exposure time on the disposition of inhaled tracer nanoparticles in the central nervous system (CNS), lung and neuroinflammatory processes, severity and progression of AD-related pathology, and functional learning and memory behaviors. Our objectives will be met with the following three specific aims to test our hypotheses: 1) define changes in the regional accumulation and retention of tracer particles in the CNS following HUCAPS exposure as a function of age and AD pathology status; 2) determine the age-related impact of HUCAPS aerosol exposures on the progression of CNS neuroinflammatory processes, AD-related pathology and cognitive decline in 3xTg-AD mice; and 3) investigate the role of TNF in HUCAPS aerosol-induced inflammatory and pathological CNS changes in 3xTg-AD mice following central or peripheral TNF blockade. Expected Results: These collaborative studies will leverage the collective expertise of two laboratories with established research programs in the fields of particulate air pollution, lung biology, neuroinflammation, and AD. These new studies are designed to learn how ambient air pollution exposures impact brain neuroinflammatory processes and AD pathogenesis and will, thus, lead to a better understanding of the effects that environmental exposures have during normative aging and in the setting of chronic neurodegeneration. The findings will have profound implications for public health policy and will enable the development of therapeutic interventions for this debilitating and costly disease.