Correlation of beta-amyloid aggregate size and hydrophobicity with decreased bilayer fluidity of model membranes.
beta-amyloid peptide (Abeta) is the primary constituent of senile plaques, a defining feature of Alzheimer's disease. Aggregated Abeta is toxic to neurons, but the mechanism of toxicity remains unproven. One proposal is that Abeta toxicity results from relatively nonspecific Abeta-membrane interactions. We hypothesized that Abeta perturbs membrane structure as a function of the aggregation state of Abeta. Toward exploring this hypothesis, Abeta 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 Abeta 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 Abeta at pH 7 did not bind bis-ANS and had little to no effect on membrane fluidity. More significantly, Abeta 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 Abeta aggregated at pH 6 than at neutral pH and were strongly correlated with the extent of decrease in membrane fluidity. Prolonged (7 days) Abeta 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 Abeta monomers into aggregates exposes hydrophobic sites and induces a decrease in membrane fluidity. Abeta aggregate-induced changes in membrane physical properties may have deleterious consequences on cellular functioning.
Kremer
J J
JJ
Department of Chemical Engineering, University of Wisconsin-Madison, 53706-1607, USA.
Pallitto
M M
MM
Sklansky
D J
DJ
Murphy
R M
RM
D016229:Amyloid beta-Peptides / Q000494:pharmacology* / Q000648:ultrastructure; D008051:Lipid Bilayers / Q000737:chemistry*; D008081:Liposomes / Q000737:chemistry*; D008560:Membrane Fluidity / Q000187:drug effects*; D010316:Particle Size
D016229:Amyloid beta-Peptides; D008051:Lipid Bilayers; D008081:Liposomes