Translational Studies on the Role of Pesticides in Cognitive Aging and AD

农药在认知衰老和 AD 中作用的转化研究

• 批准号: 9028757
• 负责人: BRENDA L PLASSMAN
• 金额: $ 40.67万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-08-13 至 2019-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9028757
• 关键词: Address; Affect; Aging; Agriculture; Alleles; Alzheimer' s Disease; Alzheimer' s disease risk; Animal Model; Area; Behavior; Behavioral; Biological Markers; Blood; Blood specimen; Brain; Chronic; Cognition; Cognitive; Cognitive aging; Collaborations; Data; Dementia; Development; Elderly; Environmental Exposure; Environmental Risk Factor; Epidemiologic Studies; Epidemiology; Exposure to; Fostering; Functional disorder; Funding; Gene Expression; Genes; Genetic; Genetic Polymorphism; Genetic Predisposition to Disease; Genotype; Grant; Health; Human; Impaired cognition; Individual; Interdisciplinary Study; Intervention; Knowledge; Lead; Learning; Link; Memory; Modeling; Mus; Neuraxis; Neurodegenerative Disorders; Neurotransmitters; Parents; Pathogenesis; Patients; Pesticides; Phenotype; Population; Prevention; Psyche structure; Public Health; Reporting; Research; Research Personnel; Risk; Risk Factors; Role; Scientist; Serum; Susceptibility Gene; Synapses; System; Toxic effect; Toxicant exposure; Toxicology; Transgenic Mice; Work; Zebrafish; base; cholinergic; cognitive change; cognitive function; cognitive performance; cohort; disability; functional disability; genome wide association study; high risk; interest; modifiable risk; molecular marker; multidisciplinary; nerve supply; neurobehavioral; neuromechanism; neurotoxicology; non-demented; organochlorine pesticide; pesticide exposure; public health relevance; research study; translational study; virtual

 DESCRIPTION (provided by applicant): Both environmental and genetic components contribute to Alzheimer's disease (AD), yet few studies have investigated the association between AD and pesticides, an ubiquitous environmental exposure which affect the central nervous system. Although DDT was banned in the U.S. in the early 1970's, two recent studies have shown that individuals with AD have higher serum levels of DDE, the metabolite of DDT, compared to non-demented older adults. One of these studies showed an interaction between DDE, APOE and cognitive function. Current understanding of the association between DDT exposure and AD is limited by knowledge gaps due to questions about the generalizability of previous findings, whether milder cognitive changes associated with DDT can be detected prior to symptomatic dementia, and the mechanisms linking DDT to AD. To address these knowledge gaps, we propose to develop a multidisciplinary consortium to explore a set of integrated aims to investigate the association between DDT and late life cognition (including AD) and the potential mechanisms underlying the deleterious effects of DDT on cognition. The aims will leverage 1) the unique strengths of the parent study, Agricultural Health Study of Memory in Aging (AHS-MA), 2) the translational potential of mice harboring human APOE polymorphisms for detecting molecular biomarkers of exposure and cognitive dysfunction, and 3) the efficiency of the zebrafish model for determining behavioral toxicity and the neural mechanisms of functional impairment. This application builds on the currently funded grant titled `Alzheimer's Disease, Genes, and Pesticide Use in the Agricultural Health Study'. Specific Aims are: 1) Examine the association between serum organochlorine pesticide levels, including DDT and DDE, with both AD and cognitive function in the AHS-MA cohort of pesticide applicators. Examine the role of APOE in this association. 2) Identify alterations in cognitive function and gene expression from humanized APOE mice exposed to DDT and determine whether altered gene expression in the blood accurately predict changes in the brain. 3) In zebrafish exposed to chronic DDT, examine cognitive function, alterations in neurotransmitters related to AD, and biomarkers of cholinergic innervation and synaptic activity. Knowledge gained from this research can be used to identify modifiable risk factors for AD and to identify mechanisms of action which may lead to developing strategies to reduce AD risk due to environmental exposures.

 描述（由申请人提供）：环境和遗传因素都会导致阿尔茨海默病 (AD)，但很少有研究调查 AD 与农药之间的关联，农药是一种影响中枢神经系统的普遍存在的环境暴露。尽管 DDT 在 1970 年代初在美国被禁止，但最近的两项研究表明，与非痴呆老年人相比，AD 患者血清中 DDE（DDT 的代谢物）水平较高。其中一项研究表明 DDE、APOE 和认知功能之间存在相互作用。目前对 DDT 暴露与 AD 之间关系的理解受到知识差距的限制，原因是对先前研究结果的普遍性、是否可以在症状性痴呆之前检测到与 DDT 相关的较轻微的认知变化，以及 DDT 与 AD 之间的联系机制等问题。为了解决这些知识差距，我们建议建立一个多学科联盟来探索一系列综合目标，以研究滴滴涕与晚年认知（包括AD）之间的关联以及滴滴涕对认知产生有害影响的潜在机制。这些目标将利用 1) 母研究“衰老记忆农业健康研究”(AHS-MA) 的独特优势，2) 携带人类 APOE 多态性的小鼠用于检测暴露和认知功能障碍的分子生物标志物的转化潜力，以及 3) 斑马鱼模型用于确定行为毒性和功能损伤的神经机制的效率。该申请建立在当前资助的题为“农业健康研究中的阿尔茨海默氏病、基因和农药使用”的拨款基础上。具体目标是： 1) 检查 AHS-MA 农药施用者队列中血清有机氯农药水平（包括 DDT 和 DDE）与 AD 和认知功能之间的关联。检查 APOE 在该关联中的作用。 2) 鉴定接触 DDT 的人源化 APOE 小鼠的认知功能和基因表达的变化，并确定血液中基因表达的改变是否能准确预测大脑的变化。 3) 在暴露于慢性 DDT 的斑马鱼中，检查认知功能、与 AD 相关的神经递质的变化以及胆碱能神经支配和突触活动的生物标志物。从这项研究中获得的知识可用于确定 AD 的可改变风险因素，并确定可能导致制定降低环境暴露导致的 AD 风险的策略的作用机制。