The concentric β-barrel hypothesis for amyloids: Models of soluble and transmembrane amyloid-β42 oligomers and channels composed of identical subunits and GM1 gangliosides.

Soluble oligomers and transmembrane channels formed by the 42-residue variant of amyloid beta (Aβ42) play key roles in Alzheimer's disease. Unfortunately, detailed structures of these assemblies have not been determined. Our group addresses this problem by developing atomic scale models. Previously we proposed that both soluble Aβ42 oligomers and transmembrane channels have symmetric concentric β-barrel structures. Here we expand this hypothesis to include GM1 gangliosides and sometimes cholesterol and lattice models of channel assemblies. The presence of GM1 gangliosides increases the toxicity of Aβ42, enhances its ability to penetrate liposome membranes, and facilitates interactions between adjacent liposomes. Although the conformations of numerous model assemblies vary, in these models the carboxyl group of GM1 always binds to side-chains of histidine 13 and/or histidine 14. Our soluble oligomer models are consistent with electron microscopy images of beaded annular protofibrils. Our models of membrane-bound assemblies are consistent with the following: freeze-fracture and atomic force microscopy images of Aβ42 in lipid bilayers, secondary structure results, the calcium hypothesis of Alzheimer's Disease, effects of lithium depletion on AD, established β-barrel theory, and energetic criteria.