School of Science, RMIT University, Bundoora, Victoria 3083, Australia.
Int J Mol Sci. 2019 Jul 19;20(14):3531. doi: 10.3390/ijms20143531.
A large-scale epidemiology study on statins previously showed that simvastatin was unique among statins in reducing the incidence of dementia. Since amyloid beta (Aβ42) is the protein that is most associated with Alzheimer's disease, this study has focused on how simvastatin influences the turnover of native Aβ42 and Aβ42 fused with green fluorescent protein (GFP), in the simplest eukaryotic model organism, . Previous studies have established that yeast constitutively producing Aβ42 fused to GFP offer a convenient means of analyzing yeast cellular responses to Aβ42. Young cells clear the GFP fusion protein and do not have green fluorescence while the older population of cells retains the fusion protein and exhibits green fluorescence, offering a fast and convenient means of studying factors that affect Aβ42 turnover. In this study the proportion of cells having GFP fused to Aβ after exposure to simvastatin, atorvastatin and lovastatin was analyzed by flow cytometry. Simvastatin effectively reduced levels of the cellular Aβ42 protein in a dose-dependent manner. Simvastatin promoted the greatest reduction as compared to the other two statins. A comparison with fluconazole, which targets that same pathway of ergosterol synthesis, suggests that effects on ergosterol synthesis do not account for the reduced amounts of Aβ42 fused to GFP. The levels of native Aβ42 following treated with simvastatin were also examined using a more laborious approach, quantitative MALDI TOF mass spectrometry. Simvastatin efficiently reduced levels of native Aβ42 from the population. This work indicates a novel action of simvastatin in reducing levels of Aβ42 providing new insights into how simvastatin exerts its neuroprotective role. We hypothesize that this reduction may be due to protein clearance.
一项关于他汀类药物的大规模流行病学研究表明，辛伐他汀是唯一能降低痴呆发生率的他汀类药物。由于淀粉样蛋白β（Aβ42）是与阿尔茨海默病最相关的蛋白质，因此这项研究集中于辛伐他汀如何影响天然 Aβ42 和与绿色荧光蛋白（GFP）融合的 Aβ42 的周转率，在最简单的真核模式生物中。以前的研究已经确定，酵母中持续产生与 GFP 融合的 Aβ42 提供了一种方便的方法来分析酵母细胞对 Aβ42 的反应。年轻细胞清除 GFP 融合蛋白，没有绿色荧光，而较老的细胞群保留融合蛋白并表现出绿色荧光，为研究影响 Aβ42 周转率的因素提供了一种快速方便的方法。在这项研究中，通过流式细胞术分析了暴露于辛伐他汀、阿托伐他汀和洛伐他汀后与 Aβ 融合的 GFP 存在于细胞中的比例。辛伐他汀以剂量依赖的方式有效降低细胞 Aβ42 蛋白的水平。与其他两种他汀类药物相比，辛伐他汀的降低效果最大。与氟康唑（一种针对同一麦角固醇合成途径的药物）进行比较表明，对麦角固醇合成的影响并不能解释与 GFP 融合的 Aβ42 减少的量。还使用更费力的方法，即定量 MALDI TOF 质谱法，研究了用辛伐他汀处理后天然 Aβ42 的水平。辛伐他汀有效地降低了该群体中天然 Aβ42 的水平。这项工作表明辛伐他汀在降低 Aβ42 水平方面具有新的作用，为辛伐他汀发挥其神经保护作用提供了新的见解。我们假设这种减少可能是由于蛋白质清除。
