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）：阿尔茨海默氏病（AD）是与进行性功能下降和痴呆有关的毁灭性神经退行性疾病。据信零星的AD病例源于遗传易感性和环境因素的结合。炎症过程被认为是发起和/或大脑内广告相关病理的组成部分，并且许多环境触发因素与AD风险增加有关。研究计划：我们假设吸入暴露于富含颗粒颗粒的环境污染（HUCAPS）气溶胶将加速与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，鉴于炎症与与AD相关的发病机理之间的联系，我们进一步假设关键炎症调节剂的拮抗作用，即肿瘤坏死因子（TNF）-A，将减少与暴露相关的病理。我们将使用特征良好的AD（3XTG-AD）遗传小鼠模型来检验我们的假设，该模型（3XTG-AD）开发了渐进的人类样β-淀粉样蛋白和Tau Tangle病理学。小鼠将暴露于使用独特的固定浓缩器系统（HUCAP）（HUCAPS）的超细颗粒中富集的与交通相关的气溶胶。我们将评估遗传背景，发育年龄和暴露后时间对中枢神经系统中吸入的示踪剂纳米颗粒（CNS），肺和神经炎症过程，与AD相关病理学的严重程度和进展以及功能性学习和记忆行为的影响。我们的目标将实现以下三个特定目的，以检验我们的假设：1）在HUCAPS暴露后，定义了CNS中示踪剂颗粒的区域积累的变化，并且随着年龄和AD病理状态的函数； 2）确定HUCAPS气溶胶暴露对CNS神经炎症过程，与AD相关的病理学和3xTG-AD小鼠的认知下降的与年龄相关的影响； 3）研究中央或周围TNF阻断后，TNF在3xTG-AD小鼠中炎症和病理中枢神经系统中的炎症和病理中枢神经系统变化的作用。预期结果：这些协作研究将利用两个实验室的集体专业知识，并在颗粒空气污染，肺部生物学，神经炎症和AD领域具有既定的研究计划。这些新研究旨在了解环境空气污染如何影响大脑神经炎症过程和AD发病机理，从而可以更好地理解环境暴露在规范性衰老和慢性神经变性的环境中所产生的影响。这些发现将对公共卫生政策产生深远的影响，并能够为这种衰弱和昂贵的疾病开发治疗干预措施。