Sub-nanosecond dynamics of phospholipid membranes interacting with polymorphic amyloid fibrils observed by elastic incoherent neutron scattering.

Amyloidosis such as Alzheimer's or Parkinson's disease is characterized by deposition of amyloid fibrils in the brain or various internal organs. The onset of amyloidosis is related to the strength of cytotoxicity caused by toxic amyloid species. In addition, amyloid fibrils show a polymorphism, , some types of fibrils are more cytotoxic than others. It is thus important to elucidate the molecular mechanism of cytotoxicity, which is ultimately caused by interactions between amyloid fibrils and cell membranes. In this study, modulation of molecular dynamics of phospholipid membranes induced by the binding of amyloid polymorphic fibrils with different levels of cytotoxicity was studied by elastic incoherent neutron scattering in a temperature range between 280 K and 310 K. The amyloid fibrils were formed by a model system of hen egg white lysozyme at pH 2.7 or 6.0 and phospholipid vesicles were formed by DMPG or DMPC. The elastic incoherent neutron scattering curves were analyzed in terms of the mean square positional fluctuations (MSPF) of atomic motions, including its distribution, as a function of temperature, which is related to molecular flexibility. The major findings are: (1) Both more and less cytotoxic fibrils decreased the molecular flexibility of DMPG. (2) While less cytotoxic fibrils decreased the molecular flexibility of DMPC, more cytotoxic fibrils increased it. (3) Close to the physiological body temperature, more cytotoxic fibrils caused larger MSPFs of both phospholipids with an enhanced motional heterogeneity. These results imply that enhanced dynamics of phospholipids is associated with the stronger cytotoxicity.