Characterization of the interactions of Alzheimer beta-amyloid peptides with phospholipid membranes.
Increasing evidence suggests that Alzheimer beta-amyloid peptides (AAPbeta) may be toxic agents in Alzheimer disease. We investigated the possibility that the toxicity may be the result of peptide-lipid interactions, involving either the cell membrane or the intracellular vesicular system. The interaction of the AAPbeta-(1-40), AAPbeta-(1-42), AAPbeta-(9-25) and AAPbeta-(25-35)-peptides with acidic and zwitterionic phospholipids was investigated by means of circular dichroism, vesicle disruption and lipid-aggregation assays. These studies were undertaken at peptide concentrations approaching in vivo levels and at physiological salt concentrations. Circular-dichroism studies demonstrate that acidic phospholipids induce a conformational change from random coil to beta structure in AAPbeta-(1-40)-peptide and AAPbeta-(1-42)-peptide at pH 6.0. In contrast, at pH 7.0, only AAPbeta-(1-42)-peptide was induced to adopt beta structure. Phosphatidylinositol was the most efficient inducer of beta structure in AAPbeta-(1-42)-peptide. To further investigate the peptide-lipid interactions, we examined the ability of the AAPbeta peptides to disrupt and/or aggregate phospholipid vesicles. These properties were found to be mediated predominantly through electrostatic interactions with the phospholipid headgroup. The data presented in this paper have implications for AAPbeta toxicity and senile-plaque formation.
McLaurin
J
J
Department of Medical Biophysics, University of Toronto, Ontario, Canada.
Chakrabartty
A
A
D000544:Alzheimer Disease / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D002417:Cattle; D002942:Circular Dichroism; D004396:Coloring Agents / Q000378:metabolism; D005452:Fluoresceins / Q000378:metabolism; D006801:Humans; D006863:Hydrogen-Ion Concentration; D008563:Membrane Lipids / Q000378:metabolism*; D010446:Peptide Fragments / Q000378:metabolism*; D010743:Phospholipids / Q000378:metabolism*; D017433:Protein Structure, Secondary; D055672:Static Electricity
D016229:Amyloid beta-Peptides; D004396:Coloring Agents; D005452:Fluoresceins; D008563:Membrane Lipids; D010446:Peptide Fragments; D010743:Phospholipids; C078592:amyloid beta-protein (1-40); C075222:amyloid beta-protein (1-42); C074636:amyloid beta-protein (25-35); C106361:amyloid beta-protein (9-25); C053897:5(6)-carboxy-2',7'-dichlorofluorescein