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

 描述（由申请人提供）：环境和遗传因素均导致阿尔茨海默病（AD），但很少有研究调查AD与农药（一种影响中枢神经系统的普遍存在的环境暴露）之间的关联。虽然DDT在20世纪70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患者的血清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。目前对滴滴涕接触与AD之间关系的理解受到知识差距的限制，这些知识差距是由于对以前研究结果的普遍性、与滴滴涕相关的轻度认知变化是否可以在症状性痴呆之前检测到以及滴滴涕与AD之间的联系机制等问题造成的。为了解决这些知识差距，我们建议建立一个多学科的联盟，探索一套综合的目标，调查滴滴涕和晚年认知（包括AD）之间的关联和潜在的机制，滴滴涕对认知的有害影响。目标将利用1）母研究的独特优势，衰老记忆的农业健康研究（AHS-MA），2）携带人类APOE多态性的小鼠的翻译潜力，用于检测暴露和认知功能障碍的分子生物标志物，以及3）斑马鱼模型用于确定行为毒性和功能障碍的神经机制的效率。该申请建立在目前资助的题为“阿尔茨海默病，基因和农药在农业健康研究中的使用”的赠款基础上。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系。研究APOE在这种关联中的作用。2)识别暴露于DDT的人源化APOE小鼠的认知功能和基因表达的改变，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相关的神经递质的改变，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的可改变的风险因素，并确定可能导致制定策略以降低环境暴露导致的AD风险的作用机制。

 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.