Abeta42-peptide assembly on lipid bilayers.
One of the major pathological features of Alzheimer's disease (AD) is the presence of extracellular amyloid plaques that are composed predominantly of the amyloid-beta peptide (Abeta). 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 Abeta42-membrane interactions using in situ atomic force microscopy and fluorescence spectroscopy. Our studies demonstrate the association of Abeta42 with planar bilayers composed of total brain lipids, which results initially in peptide aggregation and then fibre formation. Modulation of the cholesterol content is correlated with the extent of Abeta42-assembly on the bilayer surface. Although Abeta42 was not visualized directly on cholesterol-depleted bilayers, fluorescence anisotropy and fluorimetry demonstrate Abeta42-induced membrane changes. Our results demonstrate that the composition of the lipid bilayer governs the outcome of Abeta interactions.
Yip
Christopher M
CM
Department of Chemical Engineering and Applied Chemistry, Institute for Biomaterials and Biomedical Engineering and Centre for Studies in Molecular Imaging, University of Toronto, Toronto, Ontario, Canada M5S 3G9.
Darabie
Audrey A
AA
McLaurin
JoAnne
J
D016229:Amyloid beta-Peptides / Q000737:chemistry* / Q000648:ultrastructure; D001923:Brain Chemistry; D002784:Cholesterol / Q000378:metabolism; D003505:Cyclodextrins / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005454:Fluorescence Polarization; D008051:Lipid Bilayers / Q000737:chemistry*; D008560:Membrane Fluidity / Q000187:drug effects; D020894:Microfibrils / Q000648:ultrastructure; D018625:Microscopy, Atomic Force; D008854:Microscopy, Electron; D020527:Microscopy, Scanning Probe; D010446:Peptide Fragments / Q000096:biosynthesis / Q000737:chemistry* / Q000302:isolation & purification / Q000648:ultrastructure; D012995:Solubility; D013050:Spectrometry, Fluorescence; D013997:Time Factors; D047392:beta-Cyclodextrins
D016229:Amyloid beta-Peptides; D003505:Cyclodextrins; D008051:Lipid Bilayers; D010446:Peptide Fragments; D047392:beta-Cyclodextrins; C108732:methyl-beta-cyclodextrin; D002784:Cholesterol