Association of amyloid-β peptide with membrane surfaces monitored by solid state NMR

Amyloid-beta peptide (Abeta), a key substance in Alzheimer's disease (AD), is characterized by its abnormal folding into neurotoxic aggregates. Since Abeta comprises an extracellular and transmembrane domain, some of its neurotoxic actions might be exerted via interactions with neuronal membranes. Wideline and magic angle spinning (14)N and (31)P NMR have been used in combination with differential scanning calorimetry and circular dichroism spectroscopy to investigate the association between Abeta(1-40) peptide and membranes with different electrostatic surface potentials. Calorimetric measurements showed that all membrane systems were in the liquid crystalline state at 308 K. Binding of Abeta(1-40) at a 30 : 1 lipid/peptide ratio to membranes composed of neutral dimyristoyl-phosphatidylcholine (DMPC) and negatively charged dimyristoylphosphatidylglycerol (DMPG) at a 4 : 1 molar ratio is mainly driven electrostatically, reflected in characteristic changes of the isotropic (31)P chemical shift values for both lipids. In addition, the average orientation of the choline headgroup of DMPC, with its electric P(-)-N(+)(CH(3))(3) dipole, changed directly in response to the reduced negative membrane surface potential. The deviation in tilt angle of the PN vector relative to the membrane surface is manifested in the observed (14)N NMR quadrupole splitting and can therefore be described semiquantitatively. Adding Abeta(1-40) to membranes with nominal neutral surface charge, but composed of a ternary mixture of DMPC with DMPG and the cationic amphiphile didodecyidimethyl-ammonium bromide (DDAB) at a 3: 1 : 1 molar ratio revealed surprisingly electrostatic interactions visible in the NMR spectra. Since Abeta(1-40) does not bind to neutral DMPC bilayers a model is proposed, in which on a molecular level the charged residues of Abeta(1-40) peptide can interact independently with lipid headgroups of various charges in these microscopically heterogeneous systems.