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

 描述（由申请人提供）：阿尔茨海默病（AD）是美国最常见的年龄相关性神经退行性疾病。超过90%的病例是特发性的，越来越多的人认为环境因素与易感基因相互作用，影响这种疾病的发病年龄和进展。最近的流行病学研究报告了暴露于交通相关的空气污染和AD的标志性临床特征的发生之间的正相关性，包括大脑中促炎标志物的表达增加、弥漫性淀粉样斑块、神经元细胞丢失和认知受损。我们假设机动车排放的交通相关空气污染引发大脑中的炎症反应，引发或加速AD的进展。为了测试这一点，我们将使用一种独特的动物模型：TgF344大鼠，它表达赋予AD易感性的人类基因。我们将从出生后第28天开始至12个月龄，将雄性和雌性TgF 344大鼠及其野生型同窝仔暴露于直接从San弗朗西斯科地区Caldecott隧道采样的污染空气中。Caldecott隧道空气将被输送到停放在隧道附近的便携式动物饲养场中的动物。对照动物将暴露于清洁的过滤空气中。Caldecott隧道的空气将每三周收集一次， 颗粒化学表征，并将连续监测Caldecott隧道空气和清洁过滤空气的颗粒尺寸分布和浓度。将在3、6、9和12月龄的动物中评估学习和记忆以及神经炎症和AD样病理学。这些研究将提供概念验证数据，识别AD连锁遗传易感性与普遍存在的环境风险因素之间的功能相关相互作用。

 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.