Toxic Amyloid Tape: A Novel Mixed Antiparallel/Parallel Beta-Sheet Structure Formed By Abeta On Gm1 Clusters

The abnormal aggregation of amyloid beta-protein (Abeta) is considered central in the pathogenesis of Alzheimer's disease. We focused on ‘membrane-mediated’ amyloidogenesis and found that amyloid fibrils formed on monosialoganglioside GM1 clusters were more toxic than those formed in aqueous solution. In this study, we investigated the structure of the toxic fibrils by Abeta-(1-40) in detail in comparison with less toxic fibrils formed in aqueous solution. The less toxic fibrils contain in-resister parallel beta-sheets, whereas the structure of the toxic fibrils is unknown. Atomic force microscopy revealed that the toxic fibrils had a flat, tape-like morphology composed of a single beta-sheet layer. Isotope-edited infrared spectroscopy indicated that almost the entire sequence of Abeta is included in the beta-sheet. Chemical cross-linking experiments using Cys-substituted Abetas suggested that the fibrils mainly contained both in-resister parallel and 2-residue-shifted antiparallel beta-sheet structures. Solid-state NMR experiments also supported this conclusion. Thus, the toxic fibrils were found to possess a novel unique structure.