Formation of toxic Abeta(1-40) fibrils on GM1 ganglioside-containing membranes mimicking lipid rafts: polymorphisms in Abeta(1-40) fibrils.
The abnormal aggregation and deposition of amyloid beta protein (Abeta) on neuronal cells are critical to the onset of Alzheimer's disease. The entity (oligomers or fibrils) of toxic Abeta species responsible for the pathogenesis of the disease has been controversial. We have reported that the Abeta aggregates on ganglioside-rich domains of neuronal PC12 cells as well as in raft-like model membranes. Here, we identified toxic Abeta(1-40) aggregates formed with GM1-ganglioside-containing membranes. Abeta(1-40) was incubated with raft-like liposomes composed of GM1/cholesterol/sphingomyelin at 1:2:2 and 37 degrees C. After a lag period, toxic amyloid fibrils with a width of 12 nm were formed and subsequently laterally assembled with slight changes in their secondary structure as confirmed by viability assay, thioflavin-T fluorescence, circular dichroism, and transmission electron microscopy. In striking contrast, Abeta fibrils formed without membranes were thinner (6.7 nm) and much less toxic because of weaker binding to cell membranes and a smaller surface hydrophobicity. This study suggests that toxic Abeta(1-40) species formed on membranes are not soluble oligomers but amyloid fibrils and that Abeta(1-40) fibrils exhibit polymorphisms.
Okada
Takuma
T
Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan.
Ikeda
Keisuke
K
Wakabayashi
Masaki
M
Ogawa
Mariko
M
Matsuzaki
Katsumi
K
D000682:Amyloid / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000737:chemistry* / Q000378:metabolism; D000818:Animals; D002462:Cell Membrane / Q000737:chemistry*; D002784:Cholesterol / Q000737:chemistry; D005677:G(M1) Ganglioside / Q000737:chemistry*; D008081:Liposomes / Q000737:chemistry; D021962:Membrane Microdomains / Q000737:chemistry*; D016716:PC12 Cells; D010446:Peptide Fragments / Q000737:chemistry* / Q000378:metabolism; D017433:Protein Structure, Secondary; D051381:Rats
D000682:Amyloid; D016229:Amyloid beta-Peptides; D008081:Liposomes; D010446:Peptide Fragments; C078592:amyloid beta-protein (1-40); D005677:G(M1) Ganglioside; D002784:Cholesterol