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

Abstract

Co-aggregation involving different amyloidogenic sequences has been emphasized recently in the modified amyloid cascade hypothesis. Yet, molecular-level interactions between two predominant β-amyloid peptide sequences, Aβ40 and Aβ42, in the fibrillation process in membrane-mimicked environments remain unclear. Here, we report biophysical evidence that demonstrates the molecular-level interactions between Aβ40 and Aβ42 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 Aβ40 or Aβ42. Meanwhile, site-specific interactions between Aβ 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 Aβ40 alone.