Heterotypic Interactions between the 40-and 42-Residue Isoforms of β-Amyloid Peptides on Lipid Bilayer Surfaces

Co-aggregation involving different amyloidogenic sequences has been emphasized recently in the modified amyloid cascade hypothesis. Yet, molecular-level interactions between two predominant beta-amyloid peptide sequences, A beta(40 )and A beta(42), in the fibrillation process in membrane-mimicked environments remain unclear. Here, we report biophysical evidence that demonstrates the molecular-level interactions between A beta(40) and A beta(42) at the membrane-associated conucleation stage using dynamic nuclear polarization-enhanced solid-state NMR spectroscopy. These residue-specific contacts are distinguished from those reported in mature fibrils formed by either A beta(40 )or A beta(42). Meanwhile, site-specific interactions between A beta and lipid molecules and modulation of microsecond-time-scale lipid dynamics are observed, which may be responsible for the more rapid and significant membrane content leakage compared to that with A beta(40) alone.