Spontaneous insertion of Aβ42 dimers but not monomers into a cholesterol-rich lipid bilayer

The leading Alzheimer’s disease (AD) hypothesis posits that oligomers formed by amyloid β-protein (Aβ), in particular 42 residues-long Aβ42, interact with a cellular membrane, causing a cascade of events leading to neurodegeneration. The modes of Aβ42-lipid interactions are not well understood. Here, we use explicit solvent all-atom molecular dynamics (MD) to demonstrate that Aβ42 monomers interact with lipids differently than Aβ42 dimers. In our simulations, lipids in the absence and presence of Aβ42 form a lipid bilayer with a cholesterol-rich

domain, resembling a lipid raft. Whereas lipids stabilize Aβ42 monomer structure, they destabilize Aβ42 dimers. Unlike monomers which interact exclusively with solvent exposed lipid tails on one side of a bilayer, dimers exhibit additional modes of interactions with lipids, including spontaneous insertion into the cholesterol-rich domain of a bilayer and carpeting, thereby disrupting the lipid bilayer structure. Our findings provide a mechanistic explanation for why Aβ42 monomers are non-toxic and reveal that Aβ42 oligomer-induced toxicity emerges already at the stage of Aβ42 dimer formation.