Formation of toxic Abeta(1-40) fibrils on GM1 ganglioside-containing membranes mimicking lipid rafts: polymorphisms in Abeta(1-40) fibrils |
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Authors: | Okada Takuma Ikeda Keisuke Wakabayashi Masaki Ogawa Mariko Matsuzaki Katsumi |
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Institution: | Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan |
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Abstract: | 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. |
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Keywords: | Aβ amyloid β protein AD Alzheimer's disease AM acetoxymethyl ester ANS 1-anilinonaphthalene-8-sulfonate EthiD-1 ethidium homodimer-1 Mem-fibrils Aβ(1-40) fibrils formed with GM1 ganglioside-containing membranes Mic-fibrils Aβ(1-40) fibrils formed with GM1 micelles NGF nerve growth factor PBS phosphate-buffered saline PBS-t PBS with Tween-20 PC l-α-phosphatidylcholine" target="_blank">egg yolk-l-α-phosphatidylcholine SM sphingomyelin Sol-fibrils Aβ(1-40) fibrils formed in solution TEM transmission electron microscopy ThT thioflavin T |
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