Profile of changes in lipid bilayer structure caused by beta-amyloid peptide.
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 is uncertain. One hypothesis is that interactions between A beta aggregates and cell membranes mediate A beta toxicity. Previously, we described a positive correlation between the A beta aggregation state and surface hydrophobicity, and the ability of the peptide to decrease fluidity in the center of the membrane bilayer [Kremer, J. J., et al. (2000) Biochemistry 39, 10309--10318]. In this work, we report that A beta aggregates increased the steady-state anisotropy of 1,6-diphenyl-1,3,5-hexatriene (DPH) embedded in the hydrophobic center of the membrane in phospholipids with anionic, cationic, and zwitterionic headgroups, suggesting that specific charge--charge interactions are not required for A beta--membrane interactions. A beta did not affect the fluorescence lifetime of DPH, indicating that the increase in anisotropy is due to increased ordering of the phospholipid acyl chains rather than changes in water penetration into the bilayer interior. A beta aggregates affected membrane fluidity above, but not below, the lipid phase-transition temperature and did not alter the temperature or enthalpy of the phospholipid phase transition. A beta induced little to no change in membrane structure or water penetration near the bilayer surface. Overall, these results suggest that exposed hydrophobic patches on the A beta aggregates interact with the hydrophobic core of the lipid bilayer, leading to a reduction in membrane fluidity. Decreases in membrane fluidity could hamper functioning of cell surface receptors and ion channel proteins; such decreases have been associated with cellular toxicity.
Kremer
J J
JJ
Department of Chemical Engineering, University of Wisconsin-Madison, Madison, Wisconsin 53706-1607, USA.
Sklansky
D J
DJ
Murphy
R M
RM
D015081:2-Naphthylamine / Q000031:analogs & derivatives* / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000737:chemistry*; D002412:Cations / Q000378:metabolism; D004161:Diphenylhexatriene / Q000378:metabolism; D005229:Fatty Acids, Monounsaturated / Q000378:metabolism; D005454:Fluorescence Polarization; D005456:Fluorescent Dyes / Q000378:metabolism; D006801:Humans; D007848:Laurates / Q000378:metabolism; D008051:Lipid Bilayers / Q000737:chemistry* / Q000378:metabolism*; D008081:Liposomes / Q000378:metabolism; D008560:Membrane Fluidity; D010713:Phosphatidylcholines / Q000378:metabolism; D010715:Phosphatidylglycerols / Q000378:metabolism; D000644:Quaternary Ammonium Compounds / Q000378:metabolism; D013050:Spectrometry, Fluorescence; D013499:Surface Properties; D013997:Time Factors
D016229:Amyloid beta-Peptides; D002412:Cations; D005229:Fatty Acids, Monounsaturated; D005456:Fluorescent Dyes; D007848:Laurates; D008051:Lipid Bilayers; D008081:Liposomes; D010713:Phosphatidylcholines; D010715:Phosphatidylglycerols; D000644:Quaternary Ammonium Compounds; D004161:Diphenylhexatriene; C060037:1-palmitoyl-2-oleoylglycero-3-phosphoglycerol; D015081:2-Naphthylamine; C070046:1,2-dioleoyloxy-3-(trimethylammonium)propane; C028694:1-palmitoyl-2-oleoylphosphatidylcholine; C065580:laurdan