Amyloid aggregation and deposition of human islet amyloid polypeptide at membrane interfaces
Amyloid aggregation and deposition of human islet amyloid polypeptide at membrane interfaces
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DOI：
10.1111/febs.12807
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发表时间：
2014-06
期刊：
影响因子：
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通讯作者：
K. Sasahara;K. Morigaki;K. Shinya
中科院分区：
文献类型：
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作者：
K. Sasahara;K. Morigaki;K. Shinya
人胰岛淀粉样多肽（hIAPP）在胰岛内的淀粉样沉积是2型糖尿病的病理特征。大量证据表明，hIAPP的膜介导的聚集和随后的沉积与胰腺β细胞的功能障碍和死亡有关，但对hIAPP沉积的分子过程知之甚少。在这项研究中，我们检查了hIAPP在有和没有筏组分（即胆固醇和鞘磷脂）的支持平面脂质双层上的膜介导的聚集和沉积，以深入了解hIAPP诱导的膜功能障碍。使用石英晶体微天平与耗散监测，这表明增强的积累的肽到含有筏组件的双层上的hIAPP的吸附进行了研究。显微镜观察证实了由膜吸附的hIAPP形成的聚集体的生长。膜界面的检查显示，hIAPP聚集体保留了在聚集过程中与膜结合的能力，导致聚集体插入双层。我们还报道了胰岛素对hIAPP沉积的抑制作用。这些发现表明hIAPP在膜界面聚集，导致与膜相关的淀粉样蛋白沉积，并表明胰岛素在hIAPP沉积中的作用。一个假定的机制调节hIAPP沉积在膜界面进行了讨论。
Amyloid deposition of human islet amyloid polypeptide (hIAPP) within the islets of Langerhans is a pathological feature of type 2 diabetes mellitus. Substantial evidence indicates that the membrane‐mediated aggregation and subsequent deposition of hIAPP are linked to dysfunction and death of pancreatic β‐cells, but the molecular processes of hIAPP deposition are poorly understood. In this study, we examined the membrane‐mediated aggregation and deposition of hIAPP at supported planar lipid bilayers with and without raft components (i.e. cholesterol and sphingomyelin) to provide insight into hIAPP‐induced membrane dysfunction. The adsorption of hIAPP onto the bilayers was studied using a quartz crystal microbalance with dissipation monitoring, which showed enhanced accumulation of the peptide onto the bilayer containing raft components. Microscope observations demonstrated the growth of the aggregates formed from the membrane‐adsorbed hIAPP. The examination of the membrane interfaces revealed that hIAPP aggregates retained the ability to associate with the membranes during the aggregation process, resulting in insertion of the aggregates into the bilayers. We also report the inhibitory effect of insulin on the hIAPP deposition. These findings demonstrate the aggregation of hIAPP at the membrane interfaces leading to amyloid deposits associated with the membrane and suggest a role for insulin in hIAPP deposition. A presumed mechanism regulating hIAPP deposition at the membrane interfaces is discussed.