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

描述(申请人提供)：阿尔茨海默病(AD)是一种破坏性的神经退行性疾病，与进行性功能衰退和痴呆症有关。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。炎症过程被认为是启动和/或在大脑内传播AD相关病理所必需的，许多环境触发因素与AD风险增加有关。研究计划：我们假设，吸入超细颗粒物浓缩型环境空气污染(HUCAPS)气溶胶将加速AD相关的病理，早期生命暴露将导致比成年后期暴露更严重的病理。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，拮抗关键的炎症调节因子，即肿瘤坏死因子-a，将减轻暴露相关的病理。我们将使用一种特征良好的阿尔茨海默病(3xTg-AD)遗传小鼠模型来验证我们的假设，该模型发展出类似人类的进行性β-淀粉样蛋白和tau缠结病理。老鼠将暴露在与交通相关的气溶胶中，这些气溶胶已经使用独特的固定式集中器系统(HUCAPS)浓缩了超细颗粒。我们将评估遗传背景、发育年龄和暴露后时间对吸入示踪纳米颗粒在中枢神经系统(CNS)的处置、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。我们的目标将达到以下三个特定目的，以验证我们的假设：1)确定HUCAPS暴露后中枢神经系统示踪颗粒区域积累和滞留的变化随年龄和AD病理状态的变化；2)确定HUCAPS气雾剂暴露对3xTg-AD小鼠的中枢神经系统炎症进程、AD相关病理和认知功能下降的年龄相关影响；以及3)研究肿瘤坏死因子在中枢或外周肿瘤坏死因子阻断后HUCAPS气雾剂诱导的3xTg-AD小鼠中枢神经系统炎症和病理改变中的作用。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，这些实验室在颗粒物空气污染、肺部生物学、神经炎症和AD领域都有既定的研究计划。这些新的研究旨在了解环境空气污染暴露如何影响脑神经炎症过程和AD的发病机制，从而有助于更好地理解环境暴露在正常衰老和慢性神经变性的背景下所产生的影响。这些发现将对公共卫生政策产生深远影响，并将使这种虚弱和昂贵的疾病的治疗干预措施得以发展。

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.