Membrane destabilization induced by beta-amyloid peptide 29-42: importance of the amino-terminus

Increasing evidence implicates interactions between Aβ-peptides and membrane lipids in Alzheimer's disease. To gain insight into the potential role of the free amino group of the N-terminus of Aβ29-42 fragment in these processes, we have investigated the ability of Aβ29-42 unprotected and Aβ29-42 N-protected to interact with negatively-charged liposomes and have calculated the interaction with membrane lipids by conformational analysis. Using vesicles mimicking the composition of neuronal membranes, we show that both peptides have a similar capacity to induce membrane fusion and permeabilization. The fusogenic effect is related to the appearance of non-bilayer structures where isotropic motions occur as shown by ³¹P and ²H NMR studies. The molecular modeling calculations confirm the experimental observations and suggest that lipid destabilization could be due to the ability of both peptides to adopt metastable positions in the presence of lipids. In conclusion, the presence of a free or protected (acetylated) amino group in the N-terminus of Aβ29-42 is therefore probably not crucial for destabilizing properties of the C-terminal fragment of Aβ peptides.