The Effects of Gene-Environment Interactions Between Cadmium Exposure and Apolipoprotein E4 on Memory in a Mouse Model of Alzheimer's Disease.
The Effects of Gene-Environment Interactions Between Cadmium Exposure and Apolipoprotein E4 on Memory in a Mouse Model of Alzheimer's Disease.
复制标题
DOI：
10.1093/toxsci/kfz218
复制
发表时间：
2019-10
期刊：
影响因子：
--
通讯作者：
Liang Zhang;Hao Wang;Glen M. Abel;D. Storm;Z. Xia
中科院分区：
文献类型：
--
作者：
Liang Zhang;Hao Wang;Glen M. Abel;D. Storm;Z. Xia
镉 (Cd) 是一种引起公众健康极大关注的重金属。最近的研究表明，镉暴露与人类认知能力下降之间存在联系。与常见的 ε3 等位基因相比，人类载脂蛋白 E 基因 (ApoE) 的 ε4 等位基因与认知能力加速下降和阿尔茨海默病风险增加相关。为了研究 ApoE-ε4 和 Cd 暴露对认知的基因-环境相互作用 (GxE)，我们使用了表达人类 ApoE-ε3 (ApoE3-KI (knock-in)) 或 ApoE-ε4 (ApoE4-KI) 的阿尔茨海默病小鼠模型。小鼠通过饮用水暴露于 0.6 mg/L CdCl2 中 14 周，并评估海马依赖性记忆。暴露后立即处死另一组，用于镉测量和免疫染色。血镉峰值为 0.3-0.4 µg/L，处于美国普通人群的水平范围内。所有接受镉处理的动物在新物体定位（NOL）测试中都表现出空间工作记忆缺陷。在同性别中，这种缺陷在 ApoE4-KI 小鼠中比 ApoE3-KI 小鼠中表现得更早，并且在相同基因型中，雄性小鼠中比雌性小鼠中表现得更早。在 T 迷宫测试中，ApoE4-KI 而非 ApoE3-KI 小鼠在生命后期表现出自发交替减少。最后，镉暴露损害了雄性 ApoE4-KI 小鼠海马体中成年神经元的神经元分化。这些数据表明，ApoE4 和 Cd 暴露之间的 GxE 会导致加速认知障碍，成人海马神经发生受损可能是潜在机制之一。此外，当动物年轻时，雄性小鼠比雌性小鼠更容易受到这种 GxE 效应的影响。
Cadmium (Cd) is a heavy metal of great public health concern. Recent studies suggested a link between Cd exposure and cognitive decline in humans. The ε4 allele, compared to the common ε3 allele, of the human apolipoprotein E gene (ApoE) is associated with accelerated cognitive decline and increased risks for Alzheimer's disease. To investigate the gene-environment interactions (GxE) between ApoE-ε4 and Cd exposure on cognition, we used a mouse model of Alzheimer's disease that expresses human ApoE-ε3 (ApoE3-KI (knock-in)) or ApoE-ε4 (ApoE4-KI). Mice were exposed to 0.6 mg/L CdCl2 through drinking water for 14 weeks, and assessed for hippocampus-dependent memory. A separate cohort was sacrificed immediately after exposure and used for Cd measurements and immunostaining. The peak blood Cd was 0.3-0.4 µg/L, within levels found in the US general population. All Cd-treated animals exhibited spatial working memory deficits in the novel object location (NOL) test. This deficit manifested earlier in ApoE4-KI mice than in ApoE3-KI within the same sex, and earlier in males than females within the same genotype. ApoE4-KI but not ApoE3-KI mice exhibited reduced spontaneous alternation later in life in the T-maze test. Finally, Cd exposure impaired neuronal differentiation of adult-born neurons in the hippocampus of male ApoE4-KI mice. These data suggest that a GxE between ApoE4 and Cd exposure leads to accelerated cognitive impairment and that impaired adult hippocampal neurogenesis may be one of the underlying mechanisms. Furthermore, male mice were more susceptible than female mice to this GxE effect when animals were young.