Metal ions, pH, and cholesterol regulate the interactions of Alzheimer's disease amyloid-β peptide with membrane lipid

The interaction of Abeta peptides with the lipid matrix of neuronal cell membranes plays an important role in the pathogenesis of Alzheimer's disease. By using EPR and CD spectroscopy, we found that in the presence of Cu2+ or Zn2+, pH, cholesterol, and the length of the peptide chain influenced the interaction of these peptides with lipid bilayers. In the presence of Zn2+, Abeta40 and Abeta42 both inserted into the bilayer over the pH range 5.5-7.5, as did Abeta42 in the presence of Cu2+. However, Abeta40 only penetrated the lipid bilayer in the presence of Cu2+ at pH 5.5-6.5; at higher pH there was a change in the Cu2+ coordination sphere that inhibited membrane insertion. In the absence of the metals, insertion of both peptides only occurred at pH < 5.5. Raising cholesterol to 0.2 mol fraction of the total lipid inhibited insertion of both peptides under all conditions investigated. Membrane insertion was accompanied by the formation of alpha-helical structures. The nature of these structures was the same irrespective of the conditions used, indicating a single low energy structure for Abeta in membranes. Peptides that did not insert into the membrane formed beta-sheet structures on the surface of the lipid.