Amyloid-ß peptide dimers undergo a random coil to ß-sheet transition in the aqueous phase but not at the neuronal membrane.

ABSTRACT

Mounting evidence suggests that the neuronal cell membrane is the main site of oligomer-mediated neuronal toxicity of amyloid-ß peptides in Alzheimer's disease. To gain a detailed understanding of the mutual interference of amyloid-ß oligomers and the neuronal membrane, we carried out microseconds of all-atom molecular dynamics (MD) simulations on the dimerization of amyloid-ß (Aß)42 in the aqueous phase and in the presence of a lipid bilayer mimicking the in vivo composition of neuronal membranes. The dimerization in solution is characterized by a random coil to ß-sheet transition that seems on pathway to amyloid aggregation, while the interactions with the neuronal membrane decrease the order of the Aß42 dimer by attenuating its propensity to form a ß-sheet structure. The main lipid interaction partners of Aß42 are the surface-exposed sugar groups of the gangliosides GM1. As the neurotoxic activity of amyloid oligomers increases with oligomer order, these results suggest that GM1 is neuroprotective against Aß-mediated toxicity.