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

Abstract

Increasing evidence suggests that Alzheimer β-amyloid peptides (AAPβ) may be toxic agents in Alzhemer 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 AAPβ-(1-40), AAPβ-(1-42), AAPβ-(9-25) and AAPβ-(25-35)-peptides with acidic and zwitter-ionic 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 β structure in AAPβ-(1-40)-peptide and AAPβ-(1-42)-peptide at pH 6.0. In contrast, at pH 7.0, only AAPβ-(1-42)-peptide was induced to adopt P structure. Phosphatidylinositol was the most efficient inducer of β structure in AAPβ-(1-42)-peptide. To further investigate the peptide-lipid interactions, we examined the ability of the AAPβ 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 AAPβ) toxicity and senile-plaque formation.