Formation of toxic Aβ(1-40) fibrils on GM1 ganglioside-containing membranes mimicking lipid rafts:: Polymorphisms in Aβ(1-40) fibrils

The abnormal aggregation and deposition of amyloid 0 protein (A beta) on neuronal cells are critical to the onset of Alzheimer's disease. The entity (oligomers or fibrils) of toxic A beta species responsible for the pathogenesis of the disease has been controversial. We have reported that the A aggregates on ganglioside-rich domains of neuronal PC12 cells as well as in raft-like model membranes. Here, we identified toxic A beta(1-40) aggregates formed with GM1-ganglioside-containing membranes. A beta (1-40) was incubated with raft-like liposomes composed of GMI/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, A beta 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 A beta(1-40) species formed on membranes are not soluble oligomers but amyloid fibrils and that A beta (1-40) fibrils exhibit polymorphisms. (C) 2008 Elsevier Ltd. All rights reserved.