GXE and Cognitive Impairment

铅是一种重金属，在美国和全球都引起了极大的公共健康担忧。除了具有发育神经毒性的特征外，累积铅暴露对成年人也有神经毒性，并可能导致成年人认知能力加速、持续下降。载脂蛋白E基因(ApoE)在人类中以三种等位基因(ε2、ε3、ε4)存在，其中载脂蛋白E-ε3等位基因(以下简称ApoE3)是最常见的等位基因。ApoE-ε4等位基因(以下简称ApoE4)与阿尔茨海默病风险增加和认知功能减退有关，即使在没有阿尔茨海默病病理的情况下也是如此。海马体是大脑中对学习和记忆，特别是空间学习至关重要的区域。成体海马神经发生是指海马齿状回中的成体神经干细胞导致成体神经元的生成和功能整合的过程。这些成年出生的神经元可以影响依赖海马体的学习和记忆。尽管成人神经发生受到各种细胞外刺激、环境以及铅和乙醇等神经毒物的调节，但关于基因-环境相互作用(GxE)对成人神经发生影响的信息很少。这项建议侧重于铅-遗传背景交互作用对成人神经发生和海马体依赖学习和记忆的影响。

Lead is a heavy metal of great public health concern in the US and globally. In addition to its well- characterized developmental neurotoxicity, cumulative lead exposure is also neurotoxic to adults and can lead to accelerated, persistent cognitive decline in adult humans. The apolipoprotein E gene (ApoE) exists as three polymorphic alleles in humans (ε2, ε3, ε4); the ApoE -ε3 allele (simplified as ApoE3 hereafter) is the most common allele. The ApoE-ε4 allele (simplified as ApoE4 hereafter) is associated with increased risk for Alzheimer’s disease, and accelerated cognitive decline even in the absence of Alzheimer’s disease pathology. The hippocampus is a region of the brain critical for learning and memory, especially spatial learning. Adult hippocampal neurogenesis is the process whereby adult neural stem cells in the dentate gyrus of the hippocampus leads to the generation and functional integration of adult-born neurons in the hippocampus. These adult-born neurons can influence hippocampus-dependent learning and memory. Although adult neurogenesis is modulated by various extracellular stimuli, by the environment, and by neurotoxicants including lead and ethanol, there is a paucity of information regarding the effect of gene-environment interactions (GxE) on adult neurogenesis. This proposal focuses on the effect of lead-genetic background interactions on adult neurogenesis and hippocampus-dependent learning and memory.