FOM Institute AMOLF, Science Park 104, 1098 XG, Amsterdam, The Netherlands.
J Am Chem Soc. 2012 Sep 12;134(36):14781-8. doi: 10.1021/ja3031664. Epub 2012 Aug 27.
Age-related diseases, like Alzheimer's disease and type 2 diabetes mellitus, are characterized by protein misfolding and the subsequent pathological deposition of fibrillized protein, also called amyloid. Several classes of amyloid-inhibitors have recently been tested, traditionally under bulk conditions. However, it has become apparent that amyloid fibrils and oligomers assemble and exert their cytotoxic effect at cellular membranes, rather than in bulk solution. Knowledge is therefore required of inhibitor activity specifically at the phospholipid membrane interface. Here we show, using surface-specific sum-frequency generation (SFG) spectroscopy and atomic force microscopy (AFM), that the commonly used (-)-epigallocatechin gallate (EGCG) is a much less efficient amyloid inhibitor at a phospholipid interface than in bulk solution. Moreover, EGCG is not able to disaggregate existing amyloid fibrils at a phospholipid interface, in contrast to its behavior in bulk. Our results show that interfaces significantly affect the efficiency of inhibition by EGCG inhibitors and should therefore be considered during the design and testing of amyloid inhibitors.
与年龄相关的疾病，如阿尔茨海默病和 2 型糖尿病，其特征是蛋白质错误折叠和随后纤维蛋白的病理性沉积，也称为淀粉样蛋白。最近已经测试了几类淀粉样蛋白抑制剂，传统上是在大量条件下进行的。然而，很明显，淀粉样纤维和低聚物在细胞膜上组装并发挥其细胞毒性作用，而不是在大量溶液中。因此，需要了解抑制剂在磷脂膜界面的特定活性。在这里，我们使用表面特定的和频发生（SFG）光谱和原子力显微镜（AFM）表明，通常使用的（-）-表没食子儿茶素没食子酸酯（EGCG）在磷脂界面上作为淀粉样蛋白抑制剂的效率远低于在大量溶液中的效率。此外，与在大量溶液中的行为相反，EGCG 不能在磷脂界面处使现有的淀粉样纤维解聚。我们的结果表明，界面会显著影响 EGCG 抑制剂的抑制效率，因此在设计和测试淀粉样蛋白抑制剂时应加以考虑。
