The Presence of Antiparallel Beta-Sheets in Toxic Fibrils Formed by ABeta on GM1 Clusters

The abnormal aggregation of amyloid β-protein (Aβ) is considered to be central in the pathogenesis of Alzheimer's disease. We have focused on ‘membrane-mediated’ amyloidogenesis because Yanagisawa et al. identified a specific form of Aβ that was bound to monosialoganglioside GM1 in brains exhibiting the early pathological changes associated with the disease. We have found that amyloid fibrils formed on GM1 clusters were more toxic than those formed in solution [1, 2]. The less toxic fibrils formed in solution are considered to be composed of in-resister parallel β-sheets, whereas the structure of the toxic fibrils is unknown, although FTIR spectra suggested the presence of antiparallel β-sheets [1, 2].In this study, we investigated the structure of the toxic fibrils in detail. Solid-state NMR measurements using site-specifically [15N, 1-13C]-labeled Aβs suggested that the fibrils contained both parallel and antiparallel β-sheet structures. Chemical cross-linking experiments using Cys-substituted Aβs also supported this conclusion. Thus, the toxic fibrils were found to possess a novel unique structure.[1] Fukunaga, S. et al., Biochemistry 51, 8125 (2012).[2] Matsuzaki, K., Acc. Chem. Res. 47, 2397 (2014).