Does air pollution increase risk of AD in a genetically susceptible animal model?

空气污染是否会增加遗传易感动物模型患 AD 的风险？

基本信息

批准号：
9126737
负责人：
Pamela J Lein
金额：
$ 23.54万
依托单位：
UNIVERSITY OF CALIFORNIA AT DAVIS
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-06-01 至 2018-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9126737
关键词：
Address Age Age of Onset Age-Months Air Air Pollution Alzheimer&apos s Disease Alzheimer&apos s disease risk Amyloid beta-Protein Amyloid beta-Protein Precursor Animal Housing Animal Model Animals Archives Area Autonomic ganglion Behavioral Biological Markers Blood Brain Breathing Cerebral cortex Characteristics Chemicals Chronic Clinical Commuting Consensus Control Animal Data Development Diesel Exhaust Diffuse Disease Progression Dose Early Onset Familial Alzheimer&apos s Disease Engineering Environmental Risk Factor Epidemiologic Studies Exhibits Exposure to Female Future Gases Genes Genetic Genetic Predisposition to Disease Gliosis Goals Hippocampus (Brain)Housing Human Impaired cognition Inbred F344 Rats Inflammatory Response Learning Link Measures Memory Modeling Monitor Motor Vehicles Nerve Degeneration Neurodegenerative Disorders Neurologic Particle Size Particulate Matter Pathogenesis Pathology Patients Performance Phenotype Populations at Risk Predisposition Public Health Rattus Reflex action Reporting Resources San Francisco Senile Plaques Sex Characteristics Source Staging Susceptibility Gene Tauopathies Testing Time Transgenic Mice Transgenic Organisms United States Vehicle Emissions age related air filter air sampling base cerebral amyloidosis exhaust gene environment interaction inflammatory marker innovation juvenile animal male mutant neuroinflammation neuron loss neuropathology neurotoxic novel overexpression particle postnatal presenilin presenilin-1 public health relevance research study response risk variant sex tau mutation traffic-related air pollution

项目摘要

DESCRIPTION (provided by applicant): Alzheimer's disease (AD) is the most prevalent age-related neurodegenerative disease in the United States. More than 90% of cases are idiopathic and there is growing consensus that environmental factors interact with genes of susceptibility to influence the age of onset and progression of this disease. Recent epidemiological studies have reported a positive correlation between exposure to traffic-related air pollution and the occurrence of the hallmark clinical characteristics of AD, including increased expression of pro-inflammatory markers in the brain, diffuse amyloid plaques, neuronal cell loss, and impaired cognition. We hypothesize that traffic- related air pollution emitted from motor vehicles triggers inflammatory responses in the brain that initiate or accelerate the progression of AD. To test this, we will use a unique animal model: the TgF344 rat, which expresses human genes that confer susceptibility to AD. We will expose male and female TgF344 rats and their wildtype littermates to polluted air sampled directly from the Caldecott tunnel in the San Francisco area beginning at postnatal day 28 to up to 12 months of age. Caldecott tunnel air will be delivered to animals housed in a portable vivarium parked adjacent to the tunnel. Control animals will be exposed to clean filtered air. Caldecott tunnel air will be collected every three weeks for gas and particle chemical characterization, and both Caldecott tunnel air and clean filtered air will be monitored continuously for particle size distribution and concentration. Learning and memory as well as neuroinflammation and AD-like pathology will be assessed in animals at 3, 6, 9 and 12 months of age. These studies will provide proof-of-concept data identifying functionally relevant interactions between AD-linked genetic susceptibilities and a ubiquitous environmental risk factor.

描述（由适用提供）：阿尔茨海默氏病（AD）是美国最普遍的与年龄有关的神经退行性疾病。超过90％的病例是特发性的，并且越来越多的共识是，环境因素与影响这种疾病的发作时代和进展的易感基因相互作用。最近的流行病学研究报告说，暴露于交通相关的空气污染与AD的标志性临床特征的发生之间存在正相关，包括大脑中促炎性标记的表达增加，弥漫性淀粉样蛋白斑块，神经元细胞损失和认知受损。我们假设从汽车发出的与交通相关的空气污染会触发大脑中引发或加速AD进展的大脑炎症反应。为了测试这一点，我们将使用独特的动物模型：TGF344大鼠，该模型表达了人类基因，以使AD敏感。我们将揭露雄性和女性TGF344大鼠及其野生型同窝仔，直接从旧金山地区的Caldecott隧道直接从28日的Caldecott隧道采样，从28年后的第二天开始，最高12个月。 Caldecott Tunnel Air将被运送到住在隧道附近的便携式植物中的动物。控制动物将暴露于清洁的过滤空气中。 Caldecott隧道空气将每三周收集一次气体和粒子化学表征，Caldecott隧道空气和清洁过滤空气都将连续监测，以进行粒度分布和浓度。在3、6、9和12个月大的动物中，将评估学习和记忆以及神经炎症和类似AD的病理学。这些研究将提供概念验证数据，以识别与广告相关的遗传敏感性和无处不在的环境风险因素之间与功能相关的相互作用。