title: Mechanism of amyloid β-protein aggregation mediated by GM1 ganglioside clusters.
abstract: It is widely accepted that the conversion of the soluble, nontoxic amyloid β-protein (Aβ) monomer to aggregated toxic Aβ rich in β-sheet structures is central to the development of Alzheimer's disease. However, the mechanism of the abnormal aggregation of Aβ in vivo is not well understood. We have proposed that ganglioside clusters in lipid rafts mediate the formation of amyloid fibrils by Aβ, the toxicity and physicochemical properties of which are different from those of amyloids formed in solution. In this paper, the mechanism by which Aβ-(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 (Aβ:GM1 ratio of less than ∼0.013), only the helical species exists. At intermediate protein densities (Aβ:GM1 ratio between ∼0.013 and ∼0.044), the helical species and aggregated β-sheets (∼15-mer) coexist. However, the β-structure is stable and does not form larger aggregates. At Aβ:GM1 ratios above ∼0.044, the β-structure is converted to a second, seed-prone β-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.
authors.affiliation: Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto 606-8501, Japan.
authors.forename: Keisuke
authors.initials: K
authors.lastname: Ikeda
authors.forename: Takahiro
authors.initials: T
authors.lastname: Yamaguchi
authors.forename: Saori
authors.initials: S
authors.lastname: Fukunaga
authors.forename: Masaru
authors.initials: M
authors.lastname: Hoshino
authors.forename: Katsumi
authors.initials: K
authors.lastname: Matsuzaki
mesh_terms: D016229:Amyloid beta-Peptides / Q000737:chemistry* / Q000378:metabolism*; D000818:Animals; D052160:Benzothiazoles; D002417:Cattle; D002942:Circular Dichroism; D005677:G(M1) Ganglioside / Q000378:metabolism*; D007700:Kinetics; D008954:Models, Biological; D011485:Protein Binding; D055550:Protein Stability; D020836:Protein Structure, Quaternary; D017433:Protein Structure, Secondary; D013696:Temperature; D013844:Thiazoles / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; D052160:Benzothiazoles; D013844:Thiazoles; C009462:thioflavin T; D005677:G(M1) Ganglioside