Mechanism of Gene Environment Interactions in Alzheimer's Disease

我们最近报道，使用特征良好的临床队列，血清DDE水平， 有机氯农药DDT在阿尔茨海默病（AD）患者血清中的含量显著升高， 与AD诊断风险增加相关。此外，携带APOE多态性和 在认知任务中，血清中DDE水平高的人表现得比血清中DDE水平低的人差。 多态性或高DDE水平。最后，我们发现DDT和DDE会增加淀粉样蛋白的水平， 前体蛋白（APP），这表明滴滴涕暴露可能有助于 根据我们的初步研究结果，本项目的目标包括：（1）确定DDT的作用机制， 暴露增加APP水平;（2）确定APOE遗传状态对DDT对Aβ影响的影响 积累和寡聚化;（3）评估DDT暴露对AD病理学的影响， APOE多态性人源化转基因小鼠模型的行为功能障碍。我们将实现 这些目标使用尖端技术的组合，包括表观遗传分析，患者特异性干细胞， 细胞和携带人类多态性的转基因小鼠。

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.