Yagi-Utsumi Maho, Dobson Christopher M
Department of Chemistry, University of Cambridge.
Biol Pharm Bull. 2015;38(10):1668-72. doi: 10.1248/bpb.b15-00466.
Among the various hereditary mutants of amyloid β (Aβ) in familial Alzheimer's disease (AD), the A21G Flemish-type mutant has unique properties showing a low aggregation propensity but progressive deposition in vascular walls. Moreover, in contrast to other familial AD cases that show extensive Aβ1-42 deposition in the brain, patients with Flemish AD predominantly exhibit the deposition of the Aβ1-40 isoform. Here we report the structural characterization of the Flemish-type mutant (A21G) in comparison with the wild-type Aβ1-40 peptide to examine the possible effects of the A21G mutation on the conformation of the Aβ1-40 isoform. The kinetic analysis of the aggregation of the peptides monitored by thioflavin T fluorescence measurement indicates that the mutation precludes the initial nucleation process of amyloid fibril formation by Aβ1-40. Spectroscopic data indicate that the Flemish-type mutant bound to aqueous micelles composed of lyso-GM1, in which the mobile N-terminal segment is tethered through the C-terminal helical segment, has reduced α-helical structure compared to the wild-type peptide. Our findings suggest that the mutational perturbation to the membrane binding properties is coupled with the changes in nucleation behavior of Aβ during its fibril formation.
在家族性阿尔茨海默病（AD）中淀粉样β蛋白（Aβ）的各种遗传性突变体中，A21G佛兰芒型突变体具有独特的性质，表现出低聚集倾向但在血管壁中进行性沉积。此外，与其他在大脑中显示广泛Aβ1-42沉积的家族性AD病例不同，佛兰芒型AD患者主要表现出Aβ1-40异构体的沉积。在此，我们报告了佛兰芒型突变体（A21G）与野生型Aβ1-40肽相比的结构特征，以研究A21G突变对Aβ1-40异构体构象的可能影响。通过硫黄素T荧光测量监测肽聚集的动力学分析表明，该突变排除了Aβ1-40形成淀粉样纤维的初始成核过程。光谱数据表明，与野生型肽相比，与由溶血神经节苷脂GM1组成的水性胶束结合的佛兰芒型突变体（其中可移动的N端片段通过C端螺旋片段连接）具有减少的α-螺旋结构。我们的研究结果表明，对膜结合特性的突变扰动与Aβ在其纤维形成过程中成核行为的变化相关联。
