Neurochemical Research ( IF 3.7 ) Pub Date : 2020-10-16 , DOI: 10.1007/s11064-020-03147-3 Eun-Joo Shin 1 , Yoon Hee Chung 2 , Naveen Sharma 1, 3 , Bao Trong Nguyen 1 , Sung Hoon Lee 4 , Sang Won Kang 5 , Seung-Yeol Nah 6 , Myung Bok Wie 7 , Toshitaka Nabeshima 8 , Ji Hoon Jeong 3 , Hyoung-Chun Kim 1
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Abstract
A growing body evidence suggests that selenium (Se) deficiency is associated with an increased risk of developing Alzheimer’s disease (AD). Se-dependent glutathione peroxidase-1 (GPx-1) of a major antioxidant enzyme, and the most abundant isoform of GPx in the brain. In the present study, we investigated whether GPx-1 is protective against memory impairments induced by beta-amyloid (Aβ) (1–42) in mice. As the alteration of protein kinase C (PKC)-mediated ERK activation was recognized in the early stage of AD, we examined whether the GPx-1 gene modulates Aβ (1–42)-induced changes in PKC and ERK levels. We observed that Aβ (1–42) treatment (400 pmol, i.c.v.) significantly decreased PKC βII expression in the hippocampus of mice. Aβ (1–42)-induced neurotoxic changes [i.e., oxidative stress (i.e., reactive oxygen species, 4-hydroxy-2-noneal, and protein carbonyl), reduced PKC βII and phospho-ERK expressions, and memory impairment under Y-maze and passive avoidance test] were more pronounced in GPx-1 knockout than in wild type mice. Importantly, exposure to a GPx-1 gene-encoded adenovirus vector (Adv-GPx-1) significantly increased GPx-1 mRNA and GPx activity in the hippocampus of GPx-1 knockout mice. Adv-GPx-1 exposure also significantly blocked the neurotoxic changes induced by Aβ (1–42) in GPx-1 knockout mice. Treatment with ERK inhibitor U0126 did not significantly change Adv-GPx-1-mediated attenuation in PKC βII expression. In contrast, treatment with PKC inhibitor chelerythrine (CHE) reversed Adv-GPx-1-mediated attenuation in ERK phosphorylation, suggesting that PKC βII-mediated ERK signaling is important for Adv-GPx-1-mediated potentials against Aβ (1–42) insult. Our results suggest that treatment with the antioxidant gene GPx-1 rescues Aβ (1–42)-induced memory impairment via activating PKC βII-mediated ERK signaling.
Graphic Abstract
中文翻译：
谷胱甘肽过氧化物酶-1敲除促进了β-淀粉样蛋白（1-42）通过抑制PKCβII介导的ERK信号转导而引起的小鼠记忆障碍。谷胱甘肽过氧化物酶-1基因编码腺病毒载体的应用
摘要
越来越多的身体证据表明，硒缺乏与罹患阿尔茨海默氏病（AD）的风险增加有关。硒依赖性谷胱甘肽过氧化物酶-1（GPx-1）是一种主要的抗氧化酶，也是大脑中GPx含量最高的同工型。在本研究中，我们研究了GPx-1是否对小鼠β-淀粉样蛋白（Aβ）（1-42）诱导的记忆障碍有保护作用。由于在AD早期就认识到蛋白激酶C（PKC）介导的ERK激活的改变，我们检查了GPx-1基因是否调节Aβ（1-42）诱导的PKC和ERK水平的变化。我们观察到Aβ（1-42）处理（400 pmol，icv）显着降低了小鼠海马中PKCβII的表达。Aβ（1-42）诱导的神经毒性变化[例如，氧化应激（例如，活性氧，4-羟基-2-壬醛，]在GPx-1敲除中比在野生型小鼠中更明显。重要的是，暴露于GPx-1基因编码的腺病毒载体（Adv-GPx-1）会显着增加GPx-1基因敲除小鼠海马中的GPx-1 mRNA和GPx活性。Adv-GPx-1暴露还显着阻断了GPx-1基因敲除小鼠中Aβ（1-42）诱导的神经毒性变化。用ERK抑制剂U0126进行的治疗并未显着改变Adv-GPx-1介导的PKCβII表达的减弱。相反，用PKC抑制剂白屈菜红碱（CHE）处理可逆转Adv-GPx-1介导的ERK磷酸化减弱，这表明PKCβII介导的ERK信号对于Adv-GPx-1介导的针对Aβ的电位很重要（1-42）侮辱。
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