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，也是最常见的 全世界痴呆症的常见原因。据估计，有 580 万 65 岁及以上的美国人 目前患有AD。目前尚无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 被认为发挥着深远的作用。然而，它们都不是疾病的唯一因素 发展和进步。迄今为止，大量的努力集中在确定 AD 的遗传因素。在越来越多的易感基因中，只有载脂蛋白 E (APOE) 已被确定为 AD 的重要贡献者。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。 环境中暴露于包括农药在内的有毒化学物质的情况日益受到关注 因其增加 AD 风险的能力而受到认可。 AD患者严重遭受 认知缺陷。海马体是 AD 中受影响最严重的大脑区域之一，也是 AD 患者的主要大脑区域。 认知功能的调节器。学习和记忆缺陷与 实验动物和人类的成年海马神经发生。最近的研究 证明 AD 患者的成年海马神经发生减少。拟除虫菊酯 杀虫剂是最广泛使用的农业和家用杀虫剂之一。最近， 我们报告说，成人反复接触相对较低剂量的溴氰菊酯（3mg/kg）会导致 小鼠严重的认知缺陷，伴有内质网应激和明显的损伤 海马神经发生。此外，APOE4 基因型与增强的 成人海马神经发生的内质网应激反应和功能障碍。在这里我们将确定 反复接触溴氰菊酯和 APOE 基因型是否相互作用导致 ER 增强 压力、海马神经发生减少以及与 AD 相关的认知功能恶化。

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.