Aβ42-Peptide Assembly on Lipid Bilayers

One of the major pathological features of Alzheimerʹs disease (AD) is the presence of extracellular amyloid plaques that are composed predominantly of the amyloid-β peptide (Aβ). Diffuse plaques associated with AD are composed predominantly of Aβ42, whereas senile plaques contain both Aβ40 and Aβ42. Recently, it has been suggested that diffuse plaque formation is initiated as a plasma membrane-bound Aβ species and that Aβ42 is the critical component. In order to investigate this hypothesis, we have examined Aβ42–membrane interactions using in situ atomic force microscopy and fluorescence spectroscopy. Our studies demonstrate the association of Aβ42 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 Aβ42-assembly on the bilayer surface. Although Aβ42 was not visualized directly on cholesterol-depleted bilayers, fluorescence anisotropy and fluorimetry demonstrate Aβ42-induced membrane changes. Our results demonstrate that the composition of the lipid bilayer governs the outcome of Aβ interactions.