3D-visualization of amyloid-β oligomer interactions with lipid membranes by cryo-electron tomography

Amyloid-beta (A beta) assemblies have been shown to bind to lipid bilayers. This can disrupt membrane integrity and cause a loss of cellular homeostasis, that triggers a cascade of events leading to Alzheimer's disease. However, molecular mechanisms of A beta cytotoxicity and how the different assembly forms interact with the membrane remain enigmatic. Here we use cryo-electron tomography (cryoET) to obtain three-dimensional nano-scale images of various A beta assembly types and their interaction with liposomes. A beta oligomers and curvilinear protofibrils bind extensively to the lipid vesicles, inserting and carpeting the upper-leaflet of the bilayer. A beta oligomers concentrate at the interface of vesicles and form a network of A beta-linked liposomes, while crucially, monomeric and fibrillar A beta have relatively little impact on the membrane. Changes to lipid membrane composition highlight a significant role for GM1-ganglioside in promoting A beta-membrane interactions. The different effects of A beta assembly forms observed align with the highlighted cytotoxicity reported for A beta oligomers. The wide-scale incorporation of A beta oligomers and curvilinear protofibrils into the lipid bilayer suggests a mechanism by which membrane integrity is lost.