Formation of Toxic Aβ(1–40) Fibrils on GM1 Ganglioside-Containing Membranes Mimicking Lipid Rafts: Polymorphisms in Aβ(1–40) Fibrils

• Published in: Journal of molecular biology 2008-10, Vol.382 (4), p.1066-1074
• Main Authors: Okada, Takuma, Ikeda, Keisuke, Wakabayashi, Masaki, Ogawa, Mariko, Matsuzaki, Katsumi
• Format: Article
• Language: English
• Subjects: Alzheimer's disease; amyloid β protein; polymorphism; raft-like membranes; toxicity
• ISSN: 0022-2836; 1089-8638
• DOI: 10.1016/j.jmb.2008.07.072

The abnormal aggregation and deposition of amyloid β protein (Aβ) on neuronal cells are critical to the onset of Alzheimer's disease. The entity (oligomers or fibrils) of toxic Aβ species responsible for the pathogenesis of the disease has been controversial. We have reported that the Aβ aggregates on ganglioside-rich domains of neuronal PC12 cells as well as in raft-like model membranes. Here, we identified toxic Aβ(1–40) aggregates formed with GM1-ganglioside-containing membranes. Aβ(1–40) was incubated with raft-like liposomes composed of GM1/cholesterol/sphingomyelin at 1:2:2 and 37 °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, Aβ 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 Aβ(1–40) species formed on membranes are not soluble oligomers but amyloid fibrils and that Aβ(1–40) fibrils exhibit polymorphisms.