Mechanism of Gene Environment Interactions in Alzheimer's Disease

阿尔茨海默病基因环境相互作用的机制

• 批准号: 9302779
• 负责人: Jason R Richardson
• 金额: $ 50.27万
• 依托单位: NORTHEAST OHIO MEDICAL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-07-01 至 2021-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9302779
• 关键词: Abeta clearance; Age-Months; Alleles; Alzheimer' s Disease; Alzheimer' s disease risk; Amyloid; Amyloid beta-Protein; Amyloid beta-Protein Precursor; Apolipoprotein E; Astrocytes; Behavioral; Cholesterol; Chronic; Clinical; Coculture Techniques; Craniocerebral Trauma; Data; Deposition; Educational Background; Environmental Risk Factor; Epigenetic Process; Exposure to; Functional disorder; Genes; Genetic; Genetic Polymorphism; Genetic Predisposition to Disease; Genetic Status; Genotype; Goals; Hippocampus (Brain); Human; Impaired cognition; Individual; Measures; Messenger RNA; Microdialysis; Mus; Neurodegenerative Disorders; Neurons; Pathogenesis; Pathology; Patients; Pharmacology; Population; Protein Isoforms; Proteins; Relative Risks; Reporting; Risk Factors; Role; Serum; Sex Education; Sodium Channel; Stem cells; Susceptibility Gene; Techniques; Testing; Transgenic Mice; abeta accumulation; amyloid pathology; base; cognitive function; cognitive task; cohort; disease diagnosis; environmental chemical; experimental study; gene environment interaction; genome wide association study; humanized mouse; induced pluripotent stem cell; insight; mental state; mouse model; mutant; neuroblastoma cell; neurotoxic; organochlorine pesticide; pesticide exposure; prevent; protein expression; voltage

Using well-characterized clinical cohorts, we recently reported that serum levels of DDE, the metabolite of the organochlorine pesticide DDT is significantly higher in the serum of Alzheimer Disease (AD) cases and is associated with increased risk of AD diagnosis. Further, individuals harboring a polymorphism in APOE and having high serum levels of DDE performed worse on a cognitive task than either those with just the polymorphism or high DDE levels. Finally, we identified that DDT and DDE increase levels of amyloid precursor protein (APP), suggesting a possible mechanism by which DDT exposure may contribute to ADBased on our initial findings, the goals of this project include: (1) identifying the mechanism by which DDT exposure increases APP levels; (2) determining the effect of APOE genetic status on the effects of DDT on Aβ accumulation and oligomerization; and (3) assessing the effects of DDT exposure on AD pathology and behavioral dysfunction in transgenic mouse models humanized for APOE polymorphisms. We will achieve these goals using a combination of cutting edge techniques including epigenetic analysis, patient-specific stem cells, and transgenic mice harboring human polymorphisms.

使用特征良好的临床队列，我们最近报道了DDE的血清水平，代谢产物