Damage of the\nPhospholipid Bilayer by Aβ42 at\nPhysiologically Relevant Peptide Concentrations

Amyloid β (Aβ) aggregates are implicated\nin the pathology\nof several neurodegenerative diseases such as Alzheimer’s disease,\nHuntington’s disease, and Parkinson’s disease, and damage\nto membranes is considered one of the pathology-related effects of\nAβ. Experiments in vitro indicate that Aβ can damage these\nmembranes; however, such experiments were performed at Aβ concentrations\nin the micromolar range, several orders above the physiologically\nrelevant conditions. Our studies with Aβ42 in the low nanomolar\nconcentrations did not reveal any damage to the supported lipid bilayer,\nquestioning this membrane damage mechanism of Aβ. However, the\nphospholipid composition can be a factor contributing to the interaction\nof Aβ with the membrane. Therefore, in this study, we investigated\nthe interaction of 50 nM Aβ42 with supported lipid bilayers\ncomposed of equimolar ratios of POPS and POPC at phospholipid concentrations\nof 0.1 and 0.25 mg/mL. Using atomic force microscopy (AFM), we observed\nthat Aβ42 induced damage to bilayers at 0.1 mg/mL, characterized\nby forming defects that grew in size and number over time. The defects\npenetrate only the upper leaflet of the bilayer, but no such defects\nwere observed at 0.25 mg/mL phospholipid concentrations. We additionally\ndetermined Young’s modulus of these bilayers as a measure of\nstiffness, and these values were 6.9 ± 3.6 MPa and 16.6 ±\n5.3 MPa for the 0.1 mg/mL and the 0.25 mg/mL bilayers, respectively.\nThese findings suggest that Aβ42’s ability to induce\nbilayer damage depends on membrane stiffness, with softer bilayers\n(0.1 mg/mL) being more susceptible to Aβ42-induced damage. The\nresults are discussed and compared with models in which Aβ42\noligomers create localized membrane damage. The implication of the\nresults to the mechanisms of the Aβ42 oligomer pathology is\ndiscussed.