Cholesterol, a modulator of membrane-associated Abeta-fibrillogenesis.
One of the major pathological features of Alzheimer's disease is the presence of extracellular amyloid plaques that are predominantly composed of the amyloid-beta peptide (Abeta). Characterisation of plaques demonstrated the predominance of two peptides differing at the carboxyl terminus by 2 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 fibre formation, this was not the case for Abeta40 where we observed preferential fibre 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 aggregation on bilayer surfaces.
McLaurin
J
J
Centre for Research in Neurodegenerative Diseases and Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada. j.mclaurin@utoronto.ca
Darabie
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Morrison
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D016229:Amyloid beta-Peptides / Q000737:chemistry / Q000378:metabolism*; D000818:Animals; D001921:Brain / Q000378:metabolism; D001923:Brain Chemistry; D002784:Cholesterol / Q000378:metabolism*; D003505:Cyclodextrins / Q000494:pharmacology; D004095:Dihydropyridines / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008051:Lipid Bilayers / Q000378:metabolism*; D008560:Membrane Fluidity; D018625:Microscopy, Atomic Force / Q000379:methods; D016874:Neurofibrillary Tangles / Q000378:metabolism*; D010446:Peptide Fragments / Q000737:chemistry / Q000378:metabolism*; D013050:Spectrometry, Fluorescence / Q000379:methods; D013997:Time Factors; D047392:beta-Cyclodextrins
D016229:Amyloid beta-Peptides; D003505:Cyclodextrins; D004095:Dihydropyridines; D008051:Lipid Bilayers; D010446:Peptide Fragments; C078592:amyloid beta-protein (1-40); C075222:amyloid beta-protein (1-42); D047392:beta-Cyclodextrins; C108732:methyl-beta-cyclodextrin; D002784:Cholesterol