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

详细信息    查看全文

• 作者：Keisuke Ikeda ; Takahiro Yamaguchi ; Saori Fukunaga ; Masaru Hoshino ; Katsumi Matsuzaki
• 刊名：Biochemistry
• 出版年：2011
• 出版时间：July 26, 2011
• 年：2011
• 卷：50
• 期：29
• 页码：6433-6440
• 全文大小：877K
• 年卷期：v.50,no.29(July 26, 2011)
• ISSN：1520-4995

文摘

It is widely accepted that the conversion of the soluble, nontoxic amyloid 尾-protein (A尾) monomer to aggregated toxic A尾 rich in 尾-sheet structures is central to the development of Alzheimer鈥檚 disease. However, the mechanism of the abnormal aggregation of A尾 in vivo is not well understood. We have proposed that ganglioside clusters in lipid rafts mediate the formation of amyloid fibrils by A尾, the toxicity and physicochemical properties of which are different from those of amyloids formed in solution. In this paper, the mechanism by which A尾-(1鈥?0) 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尾:GM1 ratio of less than 0.013), only the helical species exists. At intermediate protein densities (A尾:GM1 ratio between 0.013 and 0.044), the helical species and aggregated 尾-sheets (15-mer) coexist. However, the 尾-structure is stable and does not form larger aggregates. At A尾:GM1 ratios above 0.044, the 尾-structure is converted to a second, seed-prone 尾-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.