Sugiura Yuuki, Ikeda Keisuke, Nakano Minoru
Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama , 2630 Sugitani, Toyama 930-0194, Japan.
Langmuir. 2015 Oct 27;31(42):11549-57. doi: 10.1021/acs.langmuir.5b03332. Epub 2015 Oct 16.
Aggregation of the amyloid-β (Aβ) protein and the formation of toxic aggregates are the possible pathogenic pathways in Alzheimer's disease. Accumulating evidence suggests that lipid membranes play key roles in protein aggregation, although the intermolecular forces that drive the interactions between Aβ-(1-40) and the membranes vary in different membrane systems. Here, we observed that a high positive curvature of lipid vesicles with diameters of ∼30 nm enhanced the association of Aβ with anionic phosphatidylglycerol membranes in the liquid-crystalline phase and with zwitterionic phosphatidylcholine membranes in the gel phase. The binding modes of Aβ to these membranes differ in terms of the location of the protein on the membrane and of the protein secondary structure. The fibrillation of Aβ was accelerated in the presence of the vesicles and at high protein-to-lipid ratios. Under these conditions, the protein accumulated on the surfaces, as demonstrated by a high (10(7) M(-1)) binding constant. Our findings suggest that packing defects on membranes with high curvatures, such as the intraluminal vesicles in multivesicular bodies and the exosomes, might result in the accumulation of toxic protein aggregates.
淀粉样β蛋白（Aβ）的聚集以及有毒聚集体的形成是阿尔茨海默病可能的致病途径。越来越多的证据表明，脂膜在蛋白质聚集中起关键作用，尽管驱动Aβ-（1-40）与膜之间相互作用的分子间力在不同的膜系统中有所不同。在此，我们观察到直径约为30 nm的脂质囊泡的高正曲率增强了Aβ与液晶相中的阴离子磷脂酰甘油膜以及凝胶相中的两性离子磷脂酰胆碱膜的结合。Aβ与这些膜的结合模式在蛋白质在膜上的位置和蛋白质二级结构方面有所不同。在囊泡存在且蛋白质与脂质比例较高的情况下，Aβ的纤维化加速。在这些条件下，蛋白质积累在表面，高结合常数（10⁷ M⁻¹）证明了这一点。我们的研究结果表明，具有高曲率的膜上的堆积缺陷，如多囊泡体和外泌体中的腔内囊泡，可能导致有毒蛋白质聚集体的积累。
