QCM-D Reveals Parallel Adsorption Pathways Governing Amyloid-β Binding to LRP-1

Abstract The interaction of amyloid-β (Aβ) with the low-density lipoprotein receptor-related protein-1 (LRP-1) plays a central role in amyloid clearance, yet the molecular mechanism governing this interaction remains poorly understood. Here, quartz crystal microbalance with dissipation monitoring (QCM-D) was used to investigate the adsorption kinetics of Aβ onto immobilized LRP-1 in real time. Adsorption produced a substantial decrease in resonance frequency accompanied by an increase in dissipation, consistent with the formation of a viscoelastic protein layer. Sequential washing with phosphate-buffered saline and Hellmanex III detergent revealed two populations of adsorbed Aβ that differed markedly in their resistance to removal. To distinguish between possible kinetic mechanisms, the experimental sensorgrams were fitted using competing adsorption models. A model comprising two independent parallel adsorption pathways accurately reproduced the experimental data and yielded randomly distributed residuals, whereas a sequential adsorption–rearrangement model exhibited systematic deviations characteristic of model misspecification. Analysis across a concentration series further supported the presence of two kinetically distinguishable adsorption components. Together, these results demonstrate that Aβ binding to LRP-1 is governed by heterogeneous adsorption kinetics involving parallel interaction pathways rather than a single sequential binding mechanism, providing a more realistic framework for interpreting receptor-mediated protein adsorption.