Amyloid-βpeptide 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 amyloidβ-peptides in Alzheimer’s disease. This study aims at gaining detailed understanding of the mutual interference of amyloid-β oligomers and the neuronal membrane, which is extremely difficult to capture experimentally due to the transient nature of these interactions. To address this problem we use an aggregate of 24μs of MD simulations to investigate the dimerization of the full-length Aβ42 peptide both in solution and in the presence of a model lipid bilayer including six lipid types to mimick the composition of a neuronal cell membrane: 38% 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC), 24%, 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphoethanolamine (POPE), 5% 1-palmitoyl-2-oleoyl-sn-glycero-3-phospho-L-serine (POPS), 20% cholesterol (CHOL), 9% sphingomyelin (SM), and 4% monosialotetrahexosylgan-glioside (GM1). The dimerization in solution is characterized by a random coil to β-sheet transition that seems on-pathway to amyloid aggregation, while the interactions with the neuronal membrane decrease the order of the Aβ42 dimer by attenuating its propensity to form a β-sheet structure. The main lipid interaction partners of Aβ42 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 Aβ-mediated toxicity.