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（由适用提供）：环境和遗传成分都导致了阿尔茨海默氏病（AD），但是很少有研究研究了AD和农药之间的关联，AD和农药之间的关联是一种无处不在的环境暴露，会影响中枢神经系统。尽管DDT在1970年代初期在美国被禁止，但最近的两项研究表明，与未痴呆的老年人相比，AD患者的血清血清水平较高，即DDT的代谢产物。这些研究之一表明DDE，APOE和认知功能之间存在相互作用。由于有关先前发现的普遍性的问题，当前对DDT暴露与AD之间关联的理解受到知识差距的限制，是否可以在症状性痴呆之前检测到与DDT相关的Miller认知变化，以及将DDT与AD联系起来的机制。为了解决这些知识差距，我们建议开发一个多学科财团，以探索一系列综合目的，以调查滴滴涕与晚期认知（包括AD）之间的关联以及DDT对认知对认知有害影响的潜在机制。目的将利用1）父母研究的独特优势，对衰老中记忆的农业健康研究（AHS-MA），2）具有人类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，以及对Zebrafish模型的效率的效率和确定性行为毒性的效率。该申请基于当前资助的赠款，标题为“农业健康研究中的阿尔茨海默氏病，基因和农药使用”。具体目的是：1）检查包括DDT和DDE在内的血清有机氯水平之间的关联与AHS-MA农药施用剂中的AD和认知功能之间的关联。检查APOE在该关联中的作用。 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改变，并确定血液中基因表达是否会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神经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识别AD的可修改风险因素，并确定行动机制，这可能导致制定策略，以降低由于环境暴露而导致的AD风险。