Kinetic study of Aβ(1-42) amyloidosis in the presence of ganglioside-containing vesicles
Kinetic study of Aβ(1-42) amyloidosis in the presence of ganglioside-containing vesicles
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含有神经节苷脂的囊泡存在时 A beta(1-42) 淀粉样变性的动力学研究
DOI：
10.1016/j.colsurfb.2019.110615
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发表时间：
2020-01-01
影响因子：
5.8
通讯作者：
Sun, Taolei
中科院分区：
文献类型：
--
作者：
Dai, Yanping;Zhang, Mingxi;Sun, Taolei
阿尔茨海默病（Alzheimer's disease，AD）的特征是淀粉样蛋白β肽（amyloid-beta peptide，A β）错误折叠，在脑中形成异常的淀粉样蛋白聚集体。虽然最近的证据表明，淀粉样蛋白沉积在体内是高度相关的生物膜，如何神经元膜的特征脂质成分介导这一过程仍有待充分阐明。在此，我们建立了模拟外泌体的囊泡模型，并研究了它们对A β（1-42）淀粉样变性动力学的影响。通过使用由三种脑脂质单唾液酸神经节苷脂GM 1、胆固醇和鞘磷脂组成的三元囊泡，我们发现GM 1可以通过促进A β（1-42）的构象转变来调节肽纤维化，并进一步定量分析了含有GM 1的囊泡对A β（1-42）纤维化动力学的影响。此外，含有GM 1的囊泡在低浓度下诱导A β（1-42）原纤维的形成，这些原纤维对PC 12细胞具有毒性。通过在分子水平上分析GM 1在这种膜的三元混合物中的作用，我们证实了GM 1簇作为肽的附着位点，从而促进A β（1-42）的原纤化。
Alzheimer's disease (AD) is characterized by the amyloid-beta peptide (A beta) misfolding to form aberrant amyloid aggregates in the brain. Although recent evidence implicates that amyloid deposition in vivo is highly related to biomembranes, how the characteristic lipid components of neuronal membranes mediate this process remains to be fully elucidated. Herein, we established vesicle models to mimic exosomes and investigated their influence on the kinetics of A beta(1-42) amyloidosis. By using ternary vesicles composed of three brain lipids monosialoganglioside GM1, cholesterol and sphingomyelin, we found that GM1 could regulate peptide fibrillation by facilitating the conformational transition of A beta(1-42), and further quantitatively analyzed the influence of GM1-containing vesicles on the kinetics of A beta(1-42) fibrillation. In addition, GM1-containing vesicles induced the formation of A beta(1-42) fibrils at low concentrations, and these fibrils were toxic to PC12 cells. By analyzing the role of GM1 in this ternary mixture of membranes at the molecular level, we confirmed that GM1 clusters are presented as attachment sites for peptides, thus promoting the fibrillation of A beta(1-42).