Gene-Pyrethroid Interaction in Alzheimer's disease

阿尔茨海默病中的基因-拟除虫菊酯相互作用

• 批准号: 10289120
• 负责人: Muhammad M Hossain
• 金额: $ 31.67万
• 依托单位: FLORIDA INTERNATIONAL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-12-07 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10289120
• 关键词: Accounting; Adult; Affect; Age; Agriculture; Alleles; Alzheimer' s Disease; Alzheimer' s disease patient; Alzheimer' s disease risk; American; Animals; Apolipoprotein E; Area; Attention; Behavioral; Brain; Brain Diseases; Cardiovascular Diseases; Cognition; Cognitive; Cognitive deficits; Cohort Studies; Dementia; Development; Disease; Dose; Drops; Environmental Exposure; Enzymes; Exposure to; Failure; Financial Hardship; Functional disorder; Future; Genes; Genetic; Genetic Predisposition to Disease; Genetic Risk; Genotype; Hippocampus (Brain); Household; Human; Impaired cognition; Impairment; Individual; Insecticides; Late Onset Alzheimer Disease; Learning; Life; Malignant Neoplasms; Mediating; Memory; Memory impairment; Mus; Nerve Degeneration; Neurons; Occupational Exposure; Organophosphates; Pathway interactions; Patients; Persons; Pesticides; Play; Poison; Population; Process; Quality of life; Reporting; Risk; Role; Serum; Susceptibility Gene; Testing; adult neurogenesis; apolipoprotein E-4; base; biological adaptation to stress; carboxylesterase; cognitive function; conditioned fear; decamethrin; detoxication; endoplasmic reticulum stress; human old age (65+); inhibitor/antagonist; insight; loved ones; mortality; nerve stem cell; neurogenesis; neuronal circuitry; novel; object recognition; pesticide exposure; pyrethroid

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.

阿尔茨海默病（AD）是一种进行性神经退行性脑疾病， 全球痴呆症的常见原因估计有580万65岁及以上的美国人 目前与AD。目前还没有治愈这种疾病的方法。年龄是最大的风险 因素，但也有许多其他因素，包括环境暴露和遗传 被认为扮演着重要的角色。然而，它们中没有一个单独是疾病的唯一因素 发展和进步。到目前为止，大量的努力集中在确定 遗传因素导致AD。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的一个强有力的贡献者。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。 包括杀虫剂在内的有毒化学品在环境中的暴露日益严重， 他们被认为有能力增加AD的风险。AD患者严重患有 认知缺陷海马体是AD中最受影响的大脑区域之一，是AD的主要神经元。 认知功能的调节器。学习和记忆缺陷与以下因素有关： 成年海马神经发生在实验动物和人类。最近的研究 表明AD患者的成年海马神经发生减少。除虫菊酯 杀虫剂是最广泛使用的农业和家庭杀虫剂之一。最近， 我们报道了成年人反复暴露于相对低剂量的溴氰菊酯（3mg/kg）， 在小鼠中存在严重的认知缺陷，伴有ER应激和明显的损伤 海马神经发生的过程此外，APOE4基因型与增强的 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 重复暴露于溴氰菊酯和APOE基因型是否相互作用导致ER增强 应激、海马神经发生减少和认知功能恶化与AD相关。