Pillot T, Goethals M, Vanloo B, Lins L, Brasseur R, Vandekerckhove J, Rosseneu M
Laboratory for Lipoprotein Chemistry, University Gent, Belgium.
Eur J Biochem. 1997 Feb 1;243(3):650-9. doi: 10.1111/j.1432-1033.1997.00650.x.
C-terminal fragments of the Alzheimer amyloid peptide (amino acids 29-40 and 29-42) have physico-chemical properties related to those of the fusion peptides of viral proteins and they are able to induce the fusion of liposomes in vitro. We proposed that these properties could mediate a direct interaction of the amyloid peptide with cell membranes and account for part of the cytotoxicity of the amyloid peptide. In view of the epidemiologic and biochemical linkages between the pathology of Alzheimer's disease and apolipoprotein E (apoE) polymorphism, we examined the potential interaction between the three common apoE isoforms and the C-terminal fragments of the amyloid peptide. We show that, at low concentration, only apoE2 and apoE3 are potent inhibitors of the amyloid peptide fusogenic and aggregational properties, whereas the apoE4 isoform has no effect. We further show that the protective effect of apoE is mediated by the formation of stable apoE/amyloid peptide complexes, as determined by tryptophan emission fluorescence measurements and by gel electrophoresis. The interaction specificity between apoE2 and apoE3 and the amyloid fragments is demonstrated here, since other apolipoproteins (e.g. apolipoprotein A-I and A-II), with similar amphipathic structures, do not interact with the amyloid C-terminal fragments. Finally, we show that, reciprocally, the amyloid peptide can interact directly with the apoE2 and apoE3 isoforms to decrease or perturb their normal association with lipids. These data suggest that the 29-40 and 29-42 domains of the amyloid peptide could be critical for the amyloid-apoE interaction, and that apoE2 and apoE3 isoforms, but not apoE4, could play a protective role against the formation of amyloid aggregates and/or against their interaction with cellular membranes.
阿尔茨海默病淀粉样肽的C末端片段（氨基酸29 - 40和29 - 42）具有与病毒蛋白融合肽相关的物理化学性质，并且它们能够在体外诱导脂质体融合。我们推测这些性质可能介导淀粉样肽与细胞膜的直接相互作用，并解释了淀粉样肽细胞毒性的部分原因。鉴于阿尔茨海默病病理学与载脂蛋白E（apoE）多态性之间的流行病学和生化联系，我们研究了三种常见apoE异构体与淀粉样肽C末端片段之间的潜在相互作用。我们发现，在低浓度下，只有apoE2和apoE3是淀粉样肽融合和聚集性质的有效抑制剂，而apoE4异构体则没有作用。我们进一步表明，apoE的保护作用是由稳定的apoE/淀粉样肽复合物的形成介导的，这通过色氨酸发射荧光测量和凝胶电泳得以确定。这里证明了apoE2和apoE3与淀粉样片段之间的相互作用特异性，因为其他具有相似两亲结构的载脂蛋白（如载脂蛋白A - I和A - II）不与淀粉样C末端片段相互作用。最后，我们表明，反之，淀粉样肽可以直接与apoE2和apoE3异构体相互作用，以减少或扰乱它们与脂质的正常结合。这些数据表明，淀粉样肽的29 - 40和29 - 域对于淀粉样肽与apoE的相互作用可能至关重要，并且apoE2和apoE3异构体而非apoE4可能在防止淀粉样聚集体形成和/或防止它们与细胞膜相互作用方面发挥保护作用。
