Division of Zoonosis, Department of Microbiology and Infectious Diseases, Graduate School of Medicine, Kobe University, Kobe 650-0017, Japan.
Phys Chem Chem Phys. 2013 Jun 21;15(23):8929-39. doi: 10.1039/c3cp44517h. Epub 2013 Mar 21.
Alzheimer's disease (AD) is the most prevalent age-dependent form of dementia, characterized by extracellular amyloid deposits comprising amyloid β-peptide (Aβ) in the cerebral cortex. Increasing evidence has indicated that ganglioside GM1 (GM1) in lipid rafts plays a pivotal role in amyloid deposition of Aβ and the related cytotoxicity in AD. Despite recent efforts to characterize Aβ-lipid interactions, the effect of Aβ aggregation on dynamic properties and organization of lipid membranes is poorly understood. In this study, we examined the aggregation of Aβ on supported lipid bilayers containing raft components (i.e., cholesterol, sphingomyelin, and GM1) and its effects on the membrane properties. We showed that the lateral fluidity of membranes was significantly affected by membrane binding and subsequent aggregation of Aβ. Microscopic observations of the membrane surfaces demonstrated an enhancement in phase separation of lipids as a result of interactions between Aβ and GM1 during induced aggregation of Aβ. The uptake of GM1 into Aβ aggregates and the attendant membrane damage were also observed under a microscope when the membrane-anchored aggregates were formed. On the basis of these observations, we propose that Aβ aggregates formed in the presence of lipid membranes have a latent ability to trigger the uptake of raft components accompanied by phase separation of lipids.
阿尔茨海默病（AD）是最常见的与年龄相关的痴呆症形式，其特征是细胞外淀粉样沉积物包含大脑皮层中的淀粉样 β 肽（Aβ）。越来越多的证据表明，脂筏中的神经节苷脂 GM1（GM1）在 Aβ的淀粉样沉积和 AD 中的相关细胞毒性中起关键作用。尽管最近努力描述 Aβ-脂质相互作用，但 Aβ聚集对脂质膜的动态特性和组织的影响仍知之甚少。在这项研究中，我们研究了含有筏成分（即胆固醇、鞘磷脂和 GM1）的支撑脂质双层上 Aβ的聚集及其对膜性质的影响。我们表明，膜结合和随后的 Aβ聚集显著影响了膜的横向流动性。膜表面的微观观察表明，由于 Aβ与 GM1 之间的相互作用，脂质的相分离增强了。当形成膜锚定的聚集体时，还可以在显微镜下观察到 GM1 进入 Aβ聚集体和伴随的膜损伤。基于这些观察结果，我们提出在脂质膜存在的情况下形成的 Aβ聚集体具有潜在的能力来触发富含筏的成分的摄取以及脂质的相分离。
