ORIGINAL PAPER Metal effects on the membrane interactions of amyloid-b peptides John D. Gehman Æ Caitlin C. O’Brien Æ Fazel Shabanpoor Æ John D. Wade Æ Frances Separovic Received: 20 September 2007 / Revised: 8 November 2007 / Accepted: 20 November 2007 / Published online: 25 January 2008 Ó EBSA 2008 Abstract Ab(1–42) peptide, found as aggregated species in Alzheimer’s disease brain, is linked to the onset of dementia. We detail results of 31 P and 2 H solid-state NMR studies of model membranes with Ab peptides and the effect of metal ions (Cu 2+ and Zn 2+ ), which are found concentrated in amyloid plaques. The effects on the lipid bilayer and the peptide structure are different for mem- brane incorporated or associated peptides. Copper ions alone destabilise the lipid bilayer and induce formation of smaller vesicles, but not when Ab(1–42) is associated with the bilayer membrane. Ab(25–35), a fragment from the C- terminal end of Ab(1–42), which lacks the metal coordi- nating sites found in the full length peptide, is neurotoxic to cortical cortex cell cultures. Addition of metal ions has little effect on membrane bilayers with Ab(25–35) pep- tides. 31 P magic angle spinning NMR data show that Ab(1– 42) and Ab(1–42)-Cu 2+ complexes interact at the surface of anionic phospholipid membranes. Incorporated peptides, however, appear to disrupt the membrane more severely than associated peptides. Solid-state 13 C NMR was used to compare structural changes of Ab(1–42) to those of Ab(25–35) in model membrane systems of anionic phos- pholipids and cholesterol. The Ab peptides appeared to have an increase in b-strand structure at the C-terminus when added to phospholipid liposomes. The inclusion of Cu 2+ also influenced the observed chemical shift of resi- dues from the C-terminal half, providing structural clues for the lipid-associated Ab/metal complex. The results point to the complex pathway(s) for toxicity of the full- length peptide. Keywords Amyloid Ab  Cholesterol  Metal interactions  Peptide–lipid interactions  Phospholipid membranes  Solid-state NMR  Structure  Alzheimer’s disease Abbreviations AD Alzheimer’s disease APP Amyloid precursor protein (CP)MAS (Cross-polarisation) Magic angle spinning CQ Clioquinol CSA Chemical shift anisotropy HFIP Hexafluoroisopropanol LUV Large unilamellar vesicles MLV Multilamellar vesicles NMR Nuclear magnetic resonance (d)POPC sn-1 (deuterated) Palmitoyl, sn-2 oleoyl phosphatidylcholine POPS Palmitoyloleoylphosphatidylserine REDOR Rotational-echo double resonance SS-NMR Solid-state NMR Introduction Alzheimer’s disease (AD) is a neurodegenerative disorder (Alzheimer 1907) associated with the accumulation of the Australian Society for Biophysics Special Issue: Metals and Membranes in Neuroscience. J. D. Gehman  C. C. O’Brien  F. Shabanpoor  F. Separovic (&) School of Chemistry, Bio21 Institute, The University of Melbourne, Melbourne, VIC 3010, Australia e-mail: fs@unimelb.edu.au F. Shabanpoor  J. D. Wade Howard Florey Institute, University of Melbourne, Melbourne, VIC 3010, Australia 123 Eur Biophys J (2008) 37:333–344 DOI 10.1007/s00249-007-0251-2