Dynamical changes of phospholipid membranes caused by polymorphic amyloid fibrils studied by quasi-elastic neutron scattering

Abstract

Deposition of protein aggregates called amyloid fibrils in various organs is the hallmark of amyloidosis such as Alzheimer's disease. Due to the polymorphism of amyloid fibrils, some types of fibrils are more cytotoxic than others, which seems to be correlated with the onset and the severity of amyloidosis. However, the molecular mechanism of cytotoxicity is not well understood, where interactions between amyloid fibrils and bio-membranes play a crucial role. Here, by employing quasi-elastic neutron scattering (QENS) in combination with the state-of-the-art analytical model of phospholipid dynamics, sub-nanoscale dynamical changes of phospholipid membranes induced by amyloid polymorphic fibrils with different levels of cytotoxicity were investigated at 280 K and 310 K. As specimens, amyloid fibrils of hen egg white lysozyme formed at pH 2.7 or 6.0 and phospholipid multilamellar vesicles of DMPG were used. Analysis of the QENS spectra showed that the dynamics of the head group is modulated differently by polymorphic fibrils: at both temperatures, the head group is located further away from the lipid long axis in the presence of more cytotoxic fibrils than in the presence of less cytotoxic fibrils despite the difference in the phase of the DMPG membrane. In addition, at 310 K close to the body temperature, binding of more cytotoxic fibrils increases the frequency of local atomic motions of DMPG molecules while it does not affect slower motions. These results suggest an importance of the dynamics of the head group and the local motions of phospholipid molecules in terms of cytotoxicity.