The Local Mechanical Properties of Lipid Bilayers are Altered by Amyloid-Forming Proteins

A vast number of protein misfolding diseases are characterized by the formation of nanoscale protein aggregates generally termed amyloids. Such diseases include Alzheimer's disease (AD), Huntington's disease (HD), and type 2 diabetes. While the precise mechanism by which amyloidogenic aggregates are toxic remains unclear, various amyloid-forming proteins interact strongly with lipid membranes. We investigated how mechanical properties of model total brain lipid extract bilayers are altered when exposed to different amyloid-forming proteins (As, huntingtin, synthetic polyQ peptide, and amylin) utilizing in situ tapping mode atomic force microscopy (AFM) and scanning probe acceleration microscopy (SPAM). The advantage of the SPAM technique is that provides nanoscale spatially resolved maps of tip/sample tapping forces, which are directly correlated to mechanical properties of the surface. As a result, mechanical changes of lipid membranes can be mapped and correlated with changes in surface topography associated with protein aggregation. using this technique, we demonstrate that lipid bilayer structure is disrupted by amyloid-forming proteins. Disrupted regions of the bilayer were associated with decreased compression modulus and reduced adhesion to the AFM probe. Both of these observed mechanical changes are consistent with a decrease in the packing efficiency of the lipids within the bilayer. The interpretation of the mechanical changes in the lipid bilayers as measured by the SPAM technique were validated via numerical simulations of the tip/surface force interaction under a variety of conditions. These changes in bilayer mechanical properties associated with exposure to amyloid forming proteins may represent a common mechanism leading to membrane dysfunction in protein misfolding diseases.