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

环境超细颗粒暴露对阿尔茨海默病进展的影响

基本信息

批准号：
8731894
负责人：
Alison Elder
金额：
$ 33.86万
依托单位：
UNIVERSITY OF ROCHESTER
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-09-09 至 2018-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8731894
关键词：
Adult Aerosols Affect Age Aging Air Pollutants Air Pollution Alzheimer&apos s Disease Alzheimer&apos s disease risk Amyloid Amyloid beta-Protein Analytical Chemistry Animal Model Animals Behavior Behavior Therapy Behavioral Biology Brain Brain Pathology Brain region Breathing Caliber Chronic Complex Mixtures Data Dementia Deposition Development Diagnosis Disease Disease Progression Dominant-Negative Mutation Elderly Environmental Exposure Environmental Impact Environmental Risk Factor Epidemiology Exhibits Exposure to Gases Genetic Genetic Predisposition to Disease Genetic Transcription Genotype Health Policy Hippocampus (Brain)Human Impaired cognition Individual Inflammation Inflammation Mediators Inflammatory Inhalation Exposure Interruption Intervention Laboratories Lead Learning Life Link Literature Lung Mediating Memory Messenger RNA Metals Methodology Modeling Molecular Biology Mus Nerve Degeneration Neuraxis Neurodegenerative Disorders Neurofibrillary Tangles Neuroglia Particulate Pathogenesis Pathology Peripheral Phase Process Property Public Health Quality of life Receptor Signaling Research Research Design Rodent Role Severities Severity of illness Source Symptoms Synapses System Testing Therapeutic Therapeutic Intervention Time Toxicology Tracer Transgenic Mice Transgenic Organisms Tumor Necrosis Factor Receptor Tumor Necrosis Factor-alpha age related base chemokine cognitive function cytokine design early life exposure effective intervention extracellular functional decline improved inflammatory marker long term memory manganese oxide meetings mouse model nanoparticle neurofibrillary tangle formation neuroinflammation neuron loss novel diagnostics novel therapeutic intervention particle particle exposure programs protein expression public health relevance receptor expression response tau Proteins tool trafficking ultrafine particle uptake

项目摘要

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.

描述（由申请人提供）：阿尔茨海默病（AD）是一种与进行性功能衰退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大脑内引发和/或传播 AD 相关病理的重要组成部分，并且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) 气溶胶将加速与 AD 相关的病理，并且生命早期的暴露将导致比成年后期发生的暴露更严重的病理。此外，考虑到炎症与 AD 相关发病机制之间的联系，我们进一步假设关键炎症调节因子（即肿瘤坏死因子 (TNF)-a）的拮抗作用将减轻与暴露相关的病理。我们将使用一个充分表征的 AD 基因小鼠模型 (3xTg-AD) 来检验我们的假设，该模型会发展出渐进的类人 β-淀粉样蛋白和 tau 缠结病理学。小鼠将暴露于与交通相关的气溶胶中，这些气溶胶已使用独特的固定浓缩器系统（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剂纳米颗粒在中枢神经系统 (CNS) 中的分布、肺部和神经炎症过程、AD 相关病理的严重性和进展以及功能学习的影响和记忆行为。我们的目标将满足以下三个具体目标，以检验我们的假设：1）定义 HUCAPS 暴露后中枢神经系统中示踪粒子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 小鼠中枢神经系统神经炎症过程、AD 相关病理学和认知能力下降的进展的年龄相关影响； 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，以及在颗粒空气污染、肺部生物学、神经炎症和 AD 领域已建立的研究项目。这些新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对正常衰老和慢性神经退行性疾病的影响。这些发现将对公共卫生政策产生深远的影响，并将有助于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。