Abstract
Amyloid β (Aβ) aggregates are implicated in the pathology of several neurodegenerative diseases such as Alzheimer's disease, Huntington's disease, and Parkinson's disease, and damage to membranes is considered one of the pathology-related effects of Aβ. Experiments in vitro indicate that Aβ can damage these membranes; however, such experiments were performed at Aβ concentrations in the micromolar range, several orders above the physiologically relevant conditions. Our studies with Aβ42 in the low nanomolar concentrations did not reveal any damage to the supported lipid bilayer, questioning this membrane damage mechanism of Aβ. However, the phospholipid composition can be a factor contributing to the interaction of Aβ with the membrane. Therefore, in this study, we investigated the interaction of 50 nM Aβ42 with supported lipid bilayers composed of equimolar ratios of POPS and POPC at phospholipid concentrations of 0.1 and 0.25 mg/mL. Using atomic force microscopy (AFM), we observed that Aβ42 induced damage to bilayers at 0.1 mg/mL, characterized by forming defects that grew in size and number over time. The defects penetrate only the upper leaflet of the bilayer, but no such defects were observed at 0.25 mg/mL phospholipid concentrations. We additionally determined Young's modulus of these bilayers as a measure of stiffness, and these values were 6.9 ± 3.6 MPa and 16.6 ± 5.3 MPa for the 0.1 mg/mL and the 0.25 mg/mL bilayers, respectively. These findings suggest that Aβ42's ability to induce bilayer damage depends on membrane stiffness, with softer bilayers (0.1 mg/mL) being more susceptible to Aβ42-induced damage. The results are discussed and compared with models in which Aβ42 oligomers create localized membrane damage. The implication of the results to the mechanisms of the Aβ42 oligomer pathology is discussed.