Interaction of Alzheimer β-Amyloid Peptide(1−40) with Lipid Membranes

Abstract

The β-amyloid peptide βAP(1−40), a 40-amino acid residues peptide, is one of the major components of Alzheimer's amyloid deposits. βAP(1−40) exhibits only a limited solubility in aqueous solution and undergoes a concentration-dependent, cooperative random coil ⇄ β-structure transition for C_pep > 10 μM [Terzi, E., Hölzemann, G., and Seelig, J. (1995) J. Mol. Biol.252, 633−642]. In the presence of acidic lipid, the equilibrium is shifted further toward β-structured aggregates. We have now characterized the lipid−peptide interaction using circular dichroism (CD) spectroscopy, lipid monolayers, and deuterium and phosphorus-31 solid-state nuclear magnetic resonance (NMR). CD spectroscopy revealed a distinct interaction between βAP(1−40) and negatively charged unilamellar vesicles. In addition to the random coil ⇄ β-structured aggregate equilibrium at low lipid-to-peptide (L/P) ratios, a β-structure → α-helix transition was observed at L/P > 55. βAP(1−40) was found to insert into acidic monolayers provided the lateral pressure was low (20 mN/m). The extent of incorporation increased distinctly with the content of acidic lipid in the monolayer. However, at a lipid packing density equivalent to that of a bilayer (lateral pressure ≥ 32 mN/m), no insertion of βAP(1−40) was observed. The lipid molecular structure in the presence of βAP(1−40) was studied with NMR. Phosphatidylcholine (PC) was selectively deuterated at the choline headgroup and at the cis-double bond of the oleic acyl chain and mixed with phosphatidylglycerol (PG). Phosphorus-31 NMR showed that the lipid phase retained the bilayer structure at all lipid-to-protein ratios. Deuterium NMR revealed no change in the headgroup conformation of the choline moiety or in the flexibility and ordering of the hydrocarbon chains upon the addition of βAP(1−40). It can be concluded that βAP(1−40) binds electrostatically to the outer envelope of the polar headgroup region without penetrating between the polar groups. The data suggest a new mechanism of helix formation induced by the proper alignment of five positive charges of βAP(1−40) on the negatively charged membrane template.