Journal
JOURNAL OF MOLECULAR BIOLOGY
Volume 382, Issue 4, Pages 1066-1074Publisher
ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD
DOI: 10.1016/j.jmb.2008.07.072
Keywords
Alzheimer's disease; amyloid beta protein; raft-like membranes; toxicity; polymorphism
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Funding
- Naito Foundation, the Ono Medical Research Foundation, the Takeda Science Foundation
- Japan Society for the Promotion of Science [17-2295]
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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.
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