Department of Psychiatry, Yanbian Brain Hospital, Yanji, Jilin, 133000, China.
Department of Preventive Medicine, Medical College, Yanbian University, Yanji, Jilin, 133002, China.
Biol Trace Elem Res. 2018 Aug;184(2):442-449. doi: 10.1007/s12011-017-1162-4. Epub 2017 Oct 28.
Amyloid beta (Aβ) is the main component of the amyloid plaques that accumulate in the brains of Alzheimer patients. The present study was conducted to investigate whether the combined treatment with selenium (Se) and zinc (Zn) offers more beneficial effects than that provided by either of them alone in reversing Aβ-induced neurotoxicity in PC12 cells. Cells were pretreated with 0.1 μmol/L of Se and Zn for 4 h, after treated with 10 mmol/L Aβ for 24 h. Cells were divided into control and five treated groups, and received either 10 mmol/L Aβ10 mmol/L Aβ + 0.1 μmol/L Se, 10 mmol/L Aβ + 0.1 μmol/L Zn, 10 mmol/LAβ + 0.1 μmol/L Se + 0.1 μmol/L Zn, or 0.1 μmol/L Se + 0.1 μmol/L Zn. The result showed that cell viability was decreased in MTT metabolic rate; LDH release and MDA, HO, and NO levels were increased and the GSK-3β and phosphorylated tau protein level were increased in Aβ-treated group (P < 0.05 or P < 0.01), which whole changes were attenuated by Se and Zn and Se combined Zn. In order to evaluate whether the Se and Zn have an effect on processing pathway of amyloid precursor protein (APP), we examined the activity of γ-secretase in primary cultured cortical neuron cells. ELISA analysis showed that Se and Zn could inhibit the activity of γ-secretase. Then we also investigated the effect of Se and Zn on the Aβ concentration and APP-N-terminal fragment expression from APP695 stably transfected Chinese hamster ovary (CHO) cells. APP695 stably transfected CHO cells were treated with 0.1 μmol/L Se and Zn; cells were divided into control and four treated groups, which received either 0.5 M DAPT, 0.1 μmol/L Se, 0.1 μmol/L Zn, or 0.1 μmol/L Se + 0.1 μmol/L Zn. Se and Zn could decrease Aβ production and increase the APP-N-terminal fragment protein expression. These experiments indicate that Se and Zn have a protective effect on AD pathology that a possible mechanism is inhibiting the activity of γ-secretase to decreasing Aβ production further influencing the APP processing. Altogether, our findings may provide a novel therapeutic target to treat AD sufferers.
β淀粉样蛋白（Aβ）是阿尔茨海默病患者大脑中积累的淀粉样斑块的主要成分。本研究旨在探讨硒（Se）和锌（Zn）联合治疗是否比单独使用任何一种治疗方法更能有效逆转 PC12 细胞中 Aβ诱导的神经毒性。细胞先用 0.1μmol/L 的 Se 和 Zn 预处理 4 小时，然后用 10mmol/L 的 Aβ处理 24 小时。细胞分为对照组和 5 个处理组，分别接受 10mmol/L Aβ、10mmol/L Aβ+0.1μmol/L Se、10mmol/L Aβ+0.1μmol/L Zn、10mmol/L Aβ+0.1μmol/L Se+0.1μmol/L Zn 或 0.1μmol/L Se+0.1μmol/L Zn。结果显示，MTT 代谢率降低，细胞活力下降；LDH 释放和 MDA、HO 和 NO 水平升高，GSK-3β 和磷酸化 tau 蛋白水平升高（P<0.05 或 P<0.01），而 Se 和 Zn 以及 Se 联合 Zn 则减弱了这些变化。为了评估 Se 和 Zn 是否对淀粉样前体蛋白（APP）的加工途径有影响，我们在原代培养的皮质神经元细胞中检测了γ-分泌酶的活性。ELISA 分析表明，Se 和 Zn 可以抑制 γ-分泌酶的活性。然后，我们还研究了 Se 和 Zn 对 APP695 稳定转染中国仓鼠卵巢（CHO）细胞中 Aβ浓度和 APP-N 端片段表达的影响。用 0.1μmol/L Se 和 Zn 处理 APP695 稳定转染的 CHO 细胞；细胞分为对照组和 4 个处理组，分别接受 0.5M DAPT、0.1μmol/L Se、0.1μmol/L Zn 或 0.1μmol/L Se+0.1μmol/L Zn。Se 和 Zn 可以降低 Aβ 的产生，增加 APP-N 端片段蛋白的表达。这些实验表明，Se 和 Zn 对 AD 病理具有保护作用，其可能的机制是抑制γ-分泌酶的活性，从而减少 Aβ 的产生，进一步影响 APP 的加工。总之，我们的发现为治疗 AD 患者提供了一个新的治疗靶点。
