Menadione sodium bisulfite inhibits the toxic aggregation of amyloid-beta(1-42)
Menadione sodium bisulfite inhibits the toxic aggregation of amyloid-beta(1-42)
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甲萘醌亚硫酸氢钠抑制淀粉样蛋白-β(1-42) 的毒性聚集
DOI：
10.1016/j.bbagen.2018.07.019
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发表时间：
2018
影响因子：
3
通讯作者：
Huang Kun
中科院分区：
文献类型：
--
作者：
Zhang Yu;Zhao Yudan;Wang Zhuoyi;Gong Hao;Ma Liang;Sun Dongsheng;Yang Chen;Li Yang;Cheng Biao;Petersen Robert B;Jiang Fengchao;Liu Gongping;Huang Kun
蛋白质错误折叠和聚集与淀粉样变性有关。淀粉样蛋白-β 1-42 （a -β 42）的毒性聚集可能破坏细胞膜并导致细胞死亡，因此被认为是阿尔茨海默病（AD）的一个促成因素。1,4-萘醌（NQ）对胰岛素和α-突触核蛋白等淀粉样蛋白具有较强的抗聚集作用；但其毒性大，溶解度差，限制了其临床应用。美那酮亚硫酸氢钠（MSB，又称维生素K3）在中国临床用于治疗因维生素K缺乏引起的出血性疾病，在全球范围内作为维生素K补充剂使用。我们假设MSB可以抑制淀粉样蛋白的形成，因为它的骨架结构与NQ相似。为了验证我们的假设，我们首先在体外研究了MSB对a - β42淀粉样蛋白形成的影响。我们发现，MSB以剂量依赖的方式抑制a β42淀粉样蛋白的形成，延缓a β42从随机线圈到有序薄片的二级结构转化，并减弱a β42聚集体破坏膜的能力；此外，醌主链而不是亲脂性对MSB的抑制作用至关重要。接下来，在表达导致神经元内a β低聚物形成的致病性APP突变（大阪突变）的细胞中，MSB抑制了a β的细胞内聚集。此外，MSB处理显著延长了秀丽隐杆线虫CL2120（一种表达人a β42的菌株）的寿命。总之，这些结果表明，MSB及其衍生物可能会进一步被探索为预防或治疗AD的潜在治疗剂。
Protein misfolding and aggregation are associated with amyloidosis. The toxic aggregation of amyloid-β 1–42 (Aβ42) may disrupt cell membranes and lead to cell death and is thus regarded as a contributing factor in Alzheimer's disease (AD). 1,4-naphthoquinone (NQ) has been shown to exhibit strong anti-aggregation effects on amyloidogenic proteins such as insulin and α-synuclein; however, its high toxicity and poor solubility limit its clinical application. Menadione sodium bisulfite (MSB, also known as vitamin K3), is used clinically in China to treat hemorrhagic diseases caused by vitamin K deficiency and globally as a vitamin K supplement. We hypothesized that MSB could inhibit amyloid formation since its backbone structure is similar to NQ. To test our hypothesis, we first investigated the effects of MSB on Aβ42 amyloid formationin vitro. We found that MSB inhibited Aβ42 amyloid formation in a dose dependent manner, delayed the secondary structural conversion of Aβ42 from random coil to ordered β-sheet, and attenuated the ability of Aβ42 aggregates to disrupt membranes; moreover, the quinone backbone rather than lipophilicity is esstial for the inhibitory effects of MSB. Next, in cells expressing a pathogenic APP mutation (Osaka mutation) that results in the formation of intraneuronal Aβ oligomers, MSB inhibited the intracellular aggregation of Aβ. Moreover, MSB treatment significantly extended the life span of Caenorhabditis elegans CL2120, a strain that expresses human Aβ42. Together, these results suggest that MSB and its derivatives may be further explored as potential therapeutic agents for the prevention or treatment of AD.