Physics Graduate Program, University of Central Florida, Orlando, FL, USA.
Biotechnology Graduate Program, University of Central Florida, Orlando, FL, USA.
Sci Rep. 2019 Feb 25;9(1):2689. doi: 10.1038/s41598-019-38749-7.
The amyloid β (Aβ) peptide and its shorter variants, including a highly cytotoxic Aβ peptide, exert their neurotoxic effect during Alzheimer's disease by various mechanisms, including cellular membrane permeabilization. The intrinsic polymorphism of Aβ has prevented the identification of the molecular basis of Aβ pore formation by direct structural methods, and computational studies have led to highly divergent pore models. Here, we have employed a set of biophysical techniques to directly monitor Ca-transporting Aβ pores in lipid membranes, to quantitatively characterize pore formation, and to identify the key structural features of the pore. Moreover, the effect of membrane cholesterol on pore formation and the structure of Aβ has been elucidated. The data suggest that the membrane-embedded peptide forms 6- or 8-stranded β-barrel like structures. The 8-stranded barrels may conduct Ca ions through an inner cavity, whereas the tightly packed 6-stranded barrels need to assemble into supramolecular structures to form a central pore. Cholesterol affects Aβ pore formation by a dual mechanism, i.e., by direct interaction with the peptide and by affecting membrane structure. Collectively, our data illuminate the molecular basis of Aβ membrane pore formation, which should advance both basic and clinical research on Alzheimer's disease and membrane-associated pathologies in general.
淀粉样蛋白β（Aβ）肽及其较短变体，包括一种高度细胞毒性的 Aβ肽，通过多种机制，包括细胞膜通透性，在阿尔茨海默病中发挥其神经毒性作用。Aβ 的固有多态性阻止了通过直接结构方法鉴定 Aβ 孔形成的分子基础，并且计算研究导致了高度分歧的孔模型。在这里，我们使用了一组生物物理技术来直接监测脂质膜中的钙转运 Aβ 孔，定量表征孔形成，并鉴定孔的关键结构特征。此外，还阐明了膜胆固醇对孔形成和 Aβ结构的影响。数据表明，嵌入膜中的肽形成 6 或 8 股β桶状结构。8 股桶可能通过内腔传导 Ca 离子，而紧密堆积的 6 股桶需要组装成超分子结构以形成中央孔。胆固醇通过直接与肽相互作用和影响膜结构的双重机制影响 Aβ 孔形成。总的来说，我们的数据阐明了 Aβ 膜孔形成的分子基础，这应该推进阿尔茨海默病和一般与膜相关的病理学的基础和临床研究。
