Impact of Lipid Composition and Synergistic Effect on Aβ42 Oligomer-Induced Changes in Membrane Conductance and Microviscosity
The accumulation of the Aβ42 peptide is one of the key factors in the progression of Alzheimer’s disease, as it disrupts synaptic signaling and impairs neuronal function. Although the peptide is known to compromise plasma membrane integrity, the detailed mechanisms underlying bilayer alterations and lipid–Aβ42 interactions remain unclear. In the present study, electrochemical impedance spectroscopy and fluorescence lifetime imaging microscopy were employed to investigate the impact of oligomeric Aβ42 on model membranes that mimic the lipid composition of the outer leaflet of the neuronal plasma membrane. Our results demonstrate that the presence of SM or GM1 within a DOPC/Chol backbone is enough to facilitate Aβ42 interaction with the membrane, as evidenced by increased membrane microviscosity; however, this interaction alone is insufficient to induce permeability-enhancing defects in the membrane. Extensive disruption of bilayer integrity required the complete lipid ensemble present in the outer leaflet of the neuronal membrane-mimicking composition, indicating that not only specific lipids but also their cooperative interplay and organization within the lipid bilayer are essential for Aβ42-induced membrane permeabilization.