Mechanism of Amyloid beta-Protein Aggregation Mediated by GM1 Ganglioside Clusters

作者：Ikeda Keisuke; Yamaguchi Takahiro; Fukunaga Saori; Hoshino Masaru; Matsuzaki Katsumi^*

来源：Biochemistry, 2011, 50(29): 6433-6440.

DOI：10.1021/bi200771m

It is widely accepted that the conversion of the soluble, nontoxic amyloid beta-protein (A beta) monomer to aggregated toxic A beta rich in beta-sheet structures is central to the development of Alzheimer's disease. However, the mechanism of the abnormal aggregation of A beta in vivo is not well understood. We have proposed that ganglioside clusters in lipid rafts mediate the formation of amyloid fibrils by A beta, the toxicity and physicochemical properties of which are different from those of amyloids formed in solution. In this paper, the mechanism by which A beta-(1-40) fibrillizes in raftlike lipid bilayers composed of monosialoganglioside GM1, cholesterol, and sphingomyelin was investigated in detail on the basis of singular-value decomposition of circular dichroism data and analysis of fibrillization kinetics. At lower protein densities in the membrane (A beta:GM1 ratio of less than similar to 0.013), only the helical species exists. At intermediate protein densities (A beta:GM1 ratio between similar to 0.013 and similar to 0.044), the helical species and aggregated beta-sheets (similar to 15-mer) coexist. However, the beta-structure is stable and does not form larger aggregates. At A beta:GM1 ratios above similar to 0.044, the beta-structure is converted to a second, seed-prone beta-structure. The seed recruits monomers from the aqueous phase to form amyloid fibrils. These results will shed light on a molecular mechanism for the pathogenesis of the disease.

• 出版日期2011-7-26