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

Mounting evidence suggests that the neuronal cell membrane is the main site of oligomer-mediated neuronal toxicity of amyloid- [Formula: see text] peptides in Alzheimer’s disease. To gain a detailed understanding of the mutual interference of amyloid- [Formula: see text] oligomers and the neuronal membrane, we carried out microseconds of all-atom molecular dynamics (MD) simulations on the dimerization of amyloid- [Formula: see text] (A [Formula: see text])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 [Formula: see text]-sheet transition that seems on pathway to amyloid aggregation, while the interactions with the neuronal membrane decrease the order of the A [Formula: see text] 42 dimer by attenuating its propensity to form a [Formula: see text]-sheet structure. The main lipid interaction partners of A [Formula: see text] 42 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 A [Formula: see text]-mediated toxicity.