Aggregation of Alzheimer's Amyloid β-Peptide in Biological Membranes: A Molecular Dynamics Study
Aggregation of Alzheimer's Amyloid β-Peptide in Biological Membranes: A Molecular Dynamics Study
复制标题
DOI：
10.1021/bi400562x
复制
发表时间：
2013-07-23
期刊：
影响因子：
2.9
通讯作者：
Bevan, David R.
中科院分区：
文献类型：
--
作者：
Lemkul, Justin A.;Bevan, David R.
许多研究已经得出结论，淀粉样蛋白β-肽（A β）和细胞膜的相互作用有助于在阿尔茨海默病的进展中观察到的毒性和细胞死亡。聚集的A β物质破坏膜，导致物理不稳定和离子泄漏。此外，膜表面上A β的存在增加了肽的聚集速率，因为扩散发生在二维中，增加了肽间相互作用的可能性。分子动力学（MD）模拟已被用于研究A β在一些环境中，包括水溶液和膜。我们以前表明，单体A β（40），仍然嵌入在膜组成的最常见的脂质在细胞膜中发现，但神经节苷脂GM 1的存在促进肽释放到细胞外介质。在这里，我们探讨了两个A β（40）肽在模型膜中的相互作用，以了解聚集是否可以发生之前释放到水环境中的肽。我们发现，聚集发生，在不同程度上，在每个模型膜和聚集体，一旦形成，没有退出膜环境。这些信息可能对理解A β对膜的亲和力和阿尔茨海默病中A β毒性的机制具有重要意义。
Numerous studies have concluded that the interaction of the amyloid beta-peptide (A beta) and cellular membranes contributes to the toxicity and cell death observed in the progression of Alzheimer's disease. Aggregated A beta species disrupt membranes, leading to physical instability and ion leakage. Further, the presence of A beta on the membrane surface increases the aggregation rate of the peptide, as diffusion occurs in two dimensions, increasing the probability of interpeptide interactions. Molecular dynamics (MD) simulations have been used to investigate A beta in a number of environments, including aqueous solution and membranes. We previously showed that monomeric A beta(40), remains embedded in membranes composed of the most common lipids found in the cell membrane, but that the presence of ganglioside GM1 promotes release of the peptide into the extracellular medium. Here, we explore the interactions of two A beta(40) peptides in model membranes to understand whether aggregation can occur prior to the release of the peptide into the aqueous environment. We found that aggregation occurred, to different extents, in each of the model membranes and that the aggregates, once formed, did not exit the membrane environment. This information may have important implications for understanding the affinity of A beta for membranes and the mechanism of A beta toxicity in Alzheimer's disease.