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.