Cholesterol, a modulator of membrane-associated Abeta-fibrillogenesis.
One of the major pathological features of Alzheimer's disease (AD) is the presence of extracellular amyloid plaques that are predominantly composed of the amyloid-beta peptide (Abeta). Characterization of plaques demonstrated the predominance of two peptides differing at the carboxyl terminus by two hydrophobic amino acids, Abeta40 and Abeta42. Diffuse plaques associated with AD are composed predominantly of Abeta42, whereas senile plaques contain both Abeta40 and Abeta42. Recently, it has been suggested that diffuse plaque formation is initiated as a plasma membrane-bound Abeta species and that Abeta42 is the critical component. In order to investigate this hypothesis, we have examined Abeta40/42-lipid interactions using in situ atomic force microscopy, electron microscopy, and fluorescence anisotropy. While the association of Abeta42 with planar bilayers resulted in peptide aggregation, but no fiber formation, this was not the case for Abeta40, where we observed preferential fiber formation. Cholesterol, a key membrane component and modulating factor in AD, is inversely correlated with the extent of Abeta40/42-bilayer interaction. These results were confirmed using fluorescence anisotropy to evaluate the effect of Abeta on membrane fluidity and fluorimetry to confirm membrane integrity. Our results suggest that the enhanced amyloidogenic properties of Abeta42 are not correlated with fibril formation, but with aggregation on bilayer surfaces.
McLaurin
J
J
Centre for Research in Neurodegenerative Diseases, University of Toronto, Toronto, Ontario, Canada M5S 3G9. j.mclaurin@utoronto.ca
Darabie
A A
AA
Morrison
M R
MR
D000544:Alzheimer Disease / Q000378:metabolism* / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D002784:Cholesterol / Q000378:metabolism; D006801:Humans; D008563:Membrane Lipids / Q000378:metabolism; D016874:Neurofibrillary Tangles / Q000378:metabolism / Q000473:pathology
D016229:Amyloid beta-Peptides; D008563:Membrane Lipids; D002784:Cholesterol