Correlation of β-amyloid aggregate size and hydrophobicity with decreased bilayer fluidity of model membranes

beta-amyloid peptide (A beta) is the primary constituent of senile plaques, a defining feature of Alzheimer' s disease. Aggregated A beta is toxic to neurons, but the mechanism of toxicity remains unproven. One proposal is that A beta toxicity results from relatively nonspecific A beta-membrane interactions. We hypothesized that A beta perturbs membrane structure as a function of the aggregation state of A beta. Toward exploring this hypothesis, A beta aggregate size and hydrophobicity were characterized using dynamic and static light scattering and 1,1 -bis(4-anilino)naphthalene-5,5-disulfonic acid (bis-ANS) fluorescence. The effect of A beta aggregation state on the membrane fluidity of unilamellar liposomes was assessed by monitoring the anisotropy of the membrane-embedded fluorescent dye, 1 6-diphenyl-1,3,5-hexatriene (DPH), Unaggregated A beta at pH 7 did not bind bis-ANS and had little to no effect on membrane fluidity. More significantly, A beta aggregated at pH 6 or 7 decreased membrane fluidity in a time- and dose-dependent manner. Aggregation rate and surface hydrophobicity were considerably greater for A beta aggregated at pH 6 than at neutral pH and were strongly correlated with the extent of decrease in membrane fluidity. Prolonged (7 days) A beta aggregation resulted in a return to near-baseline levels in both bis-ANS fluorescence and DPH anisotropy at pH 7 but not at pH 6. The addition of gangliosides to the liposomes significantly increased the DPH anisotropy response. Hence, self-association of A beta monomers into aggregates exposes hydrophobic sites and induces a decrease in membrane fluidity. A beta aggregate-induced changes in membrane physical properties may have deleterious consequences on cellular functioning.