Characterization of the interactions of Alzheimer beta-amyloid peptides with phospholipid membranes

Increasing evidence suggests that Alzheimer beta-amyloid peptides (AAP beta) 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 AAP beta-(1-40), AAP beta-(1-42), AAP beta-(9-25) and AAP beta-(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 AAP beta-(1-40)-peptide and AAP beta-(1-42)-peptide at pH 6.0. In contrast, at pH 7.0, only AAP beta-(1-42)-peptide was induced to adopt beta structure. Phosphatidylinositol was the most efficient inducer of beta structure in AAP beta-(1-42)-peptide. To further investigate the peptide-lipid interactions, we examined the ability of the AAP beta 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 AAP beta toxicity and senile-plaque formation.