Gene-Pyrethroid Interaction in Alzheimer's disease

阿尔茨海默病(AD)是一种进行性神经退行性脑部疾病，是世界上 世界范围内痴呆症的共同原因。据估计，65岁及以上的美国人中有580万人 目前患有阿尔茨海默病。目前还没有治愈这种疾病的方法。年龄是最重要的风险 AD的因素，但还有许多其他因素，包括环境暴露和遗传 都被认为起着深远的作用。然而，它们都不是导致疾病的唯一因素。 发展和进步。到目前为止，大量的努力集中在确定 阿尔茨海默病的遗传因素。在不断增长的易感基因名单中，只有载脂蛋白 E(APOE)已被确定为AD的个体强大贡献者。载脂蛋白E4 (ApoE4)等位基因被认为是晚发性AD遗传风险的最高贡献者。 在环境中暴露于有毒化学品，包括杀虫剂，正日益受到 认识到他们有能力增加AD的风险。阿尔茨海默病患者患有严重的 认知缺陷。海马体是AD中受影响最严重的脑区之一，是主要的 认知功能的调节器。学习和记忆缺陷与脑电活动障碍有关 实验动物和人的成年海马神经发生。最新研究 显示阿尔茨海默病患者成年海马区神经发生减少。拟除虫菊酯 杀虫剂是使用最广泛的农业和家用杀虫剂之一。最近， 我们报告说，成年人反复接触相对较低剂量的溴氰菊酯(3 mg/kg)会导致 伴有内质网应激和显著损害的小鼠严重认知缺陷 关于海马神经发生的研究。此外，APOE4基因与增强型 内质网应激反应与成年海马神经发生功能障碍。在这里，我们将确定 反复接触溴氰菊酯和载脂蛋白E基因是否交互作用导致ER升高 与阿尔茨海默病相关的应激、海马神经发生减少和认知功能恶化。

Alzheimer’s disease (AD) is a progressive neurodegenerative brain disease and the most common cause of dementia worldwide. An estimated 5.8 million Americans age 65 and older are currently living with AD. There is currently no cure for this disease. Age is the most important risk factor for AD, but there are many other factors, including environmental exposures and genetic are thought to play a profound role. However, none of them alone is the sole factor in disease development and progression. To date, a substantial amount of effort has focused on to identify genetic contributors to AD. Among the growing list of susceptibility genes, only the apolipoprotein E (APOE) has been identified as an individual strong contributor to AD. Apolipoprotein E4 (APOE4) allele is considered to be the highest contributor of genetic risk to late onset AD. Environmental exposure to toxic chemicals, including pesticides, are increasingly being recognized for their ability to increase the risk of AD. Patients with AD seriously suffer from cognitive deficits. The hippocampus is one of the most affected brain areas in AD and is a major regulator of cognitive function. Learning and memory deficits are associated with disruption of adult hippocampal neurogenesis in experimental animals and humans. Recent studies demonstrate adult hippocampal neurogenesis is reduced in patients with AD. Pyrethroid insecticides are one of the most widely used agricultural and household insecticides. Recently, we reported that repeated adult exposure to a relatively low dose of deltamethrin (3mg/kg) causes profound cognitive deficits in mice, which was accompanied by ER stress and marked impairment of hippocampal neurogenesis. Further, the APOE4 genotype has been associated with enhanced ER stress response and dysfunction of adult hippocampal neurogenesis. Here we will determine whether repeated exposure to deltamethrin and APOE genotype interact to cause enhanced ER stress, reduced hippocampal neurogenesis and worsened cognitive function associated with AD.