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

 描述(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与杀虫剂之间的联系，杀虫剂是一种普遍存在的影响中枢神经系统的环境暴露。虽然滴滴涕在20世纪70年代初就在美国被禁止，但最近的两项研究表明，与非痴呆症老年人相比，阿尔茨海默病患者血清中滴滴涕的代谢物滴滴涕水平更高。其中一项研究表明，DDE、APOE和认知功能之间存在交互作用。目前对DDT暴露和AD之间的联系的了解受到知识差距的限制，因为对先前研究结果的概括性、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将DDT与AD联系起来的机制提出了质疑。为了弥补这些知识空白，我们建议建立一个多学科联盟，以探索一套综合目标，以调查滴滴涕与晚年认知(包括AD)之间的联系，以及滴滴涕对认知有害影响的潜在机制。这些目标将利用1)母公司研究的独特优势，即衰老中记忆的农业健康研究(AHS-MA)，2)携带人类APOE基因多态性的小鼠在检测暴露和认知功能障碍的分子生物标志物方面的翻译潜力，以及3)斑马鱼模型在确定行为毒性和功能损害的神经机制方面的效率。这项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”的赠款的基础上。具体目标是：1)在AHS-MA农药施用者队列中，检查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。检查APOE在该协会中的角色。2)确定暴露于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变化是否准确地预测大脑的变化。3)在长期接触DDT的斑马鱼中，检测认知功能、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以用来确定AD的可改变的风险因素，并确定可能导致制定减少因环境暴露而引起的AD风险的战略的行动机制。

 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.