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）是一种与进行性功能下降和痴呆相关的破坏性神经退行性疾病。散发性AD病例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脑内启动和/或传播AD相关病理的组成部分，许多环境触发因素与AD风险增加相关。研究计划：我们假设吸入暴露于富含超细颗粒的环境空气污染（HUCAPS）气溶胶将加速AD相关的病理，并且早期生活暴露将导致比成年后期发生的暴露更严重的病理。此外，鉴于炎症和AD相关发病机制之间的联系，我们进一步假设，一个关键的炎症调节因子，即肿瘤坏死因子（TNF）-α的拮抗作用，将减少与AD相关的病理。我们将使用一个充分表征的AD（3xTg-AD）遗传小鼠模型来测试我们的假设，该模型发展出进行性人类样β-淀粉样蛋白和tau缠结病理学。小鼠将暴露于交通相关的气溶胶，这些气溶胶已使用独特的固定浓缩器系统（HUCAPS）富集超细颗粒。我们将评估遗传背景、发育年龄和暴露后时间对吸入示踪剂纳米颗粒在中枢神经系统（CNS）、肺和神经炎症过程中的分布、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。我们的目标将通过以下三个具体目标来实现，以测试我们的假设：1）定义HUCAPS暴露后CNS中示踪剂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气雾剂暴露对3xTg-AD小鼠中CNS神经炎症过程、AD相关病理和认知下降的进展的年龄相关影响;和3）研究TNF在中枢或外周TNF阻断后3xTg-AD小鼠中HUCAPS气溶胶诱导的炎症和病理性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领域建立研究计划。这些新的研究旨在了解环境空气污染暴露如何影响大脑神经炎症过程和AD发病机制，从而更好地了解环境暴露在正常老化和慢性神经退行性变背景下的影响。这些发现将对公共卫生政策产生深远的影响，并将使这种使人衰弱和昂贵的疾病的治疗干预措施的发展成为可能。

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.