Membrane domains modulate Aβ1-42 oligomer interactions with Supported Lipid Bilayers: an Atomic Force Microscopy investigation
Alzheimer’s disease is a devastating pathology with an increasing number of affected individuals following the rise of the life expectancy. Amyloid peptide Aβ1-42 was identified as one of the main culprits of the disease. The peptide has been shown to create major effects on lipid membranes, including membrane fragmentation. The membrane composition has been identified as a factor that plays a pivotal role in regulating peptide/membrane interactions and several results suggest that lipid domains, or rafts, can promote peptide-induced membrane damages. In this work, we examined the effects of lipid segregation on the membrane-perturbing ability of Aβ1-42 and an oligomeric mutant (G37C), a peptide that shares common features with the suspected toxic intermediates involved in the neurodegeneration process. Atomic Force Microscopy (AFM) was used to determine the impact of these peptides on supported lipid bilayers of various compositions. In 1,2-dioleoyl-sn-glycero-3-phosphocholine/1,2-dipalmitoyl-sn-glycero-3-phosphocholine/cholesterol (DOPC/DPPC/cholesterol), and DOPC/Sphingomyelin/cholesterol ternary mixtures, two systems exhibiting liquid-liquid phase separations, it was shown that Aβ1-42 and G37C exclusively aggregated on liquid-disordered-phase domains, creating large deposits and even causing membrane fragmentation for the latter composition. Cholesterol and ganglioside GM1, the two most documented lipids in the context of Alzheimer’s disease are also considered to play a crucial role in promoting detrimental interactions with amyloid peptides. We have shown that, in model 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC) membranes, the presence of either cholesterol or GM1 in a proportion of 10 mol%, a content supposed to lead to domain formation, favoured the association of both A1-42 and G37C, leading to a harmful membrane fragmentation. The AFM results establish that the presence of domains favoured membrane perturbations induced by the amyloid peptides. It is proposed that lipid packing defects at the domain interface could act as adsorption and nucleation site for the amyloid peptides. The more extensive bilayer perturbations induced by G37C compared to Aβ1-42 supports the hypothesis indicating oligomers that cannot mature to the fibril state can present a considerable toxicity.