Solid-state NMR sequential assignment of Osaka-mutant amyloid-beta (Aβ1−40 E22Δ) fibrils
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Alzheimer’s disease (AD) is the most common form of dementia. Aggregation of amyloid β (Aβ), a peptide of 39−43 residues length, into insoluble fibrils is considered to initiate the disease. Determination of the molecular structure of Aβ fibrils is technically challenging and is a significant goal in AD research that may lead to design of effective therapeutical inhibitors of Aβ aggregation. Here, we present chemical-shift assignments for fibrils formed by highly pure recombinant Aβ1−40 with the Osaka E22Δ mutation that is found in familial AD. We show that that all regions of the peptide are rigid, including the N-terminal part often believed to be flexible in Aβ wt.
KeywordsAlzheimer’s disease Solid-state NMR spectroscopy Amyloid beta Amyloid structures Fibrils
We would like to thank Andreas Hunkeler for technical support and Hiang Dreher-Teo for providing TEV protease. This work was supported by the Agence Nationale de la Recherche (ANR-12-BS08-0013-01), the ETH Zurich, the Swiss National Science Foundation (Grants 200020_124611, 200020_146757) and the NCCR program “Neural Plasticity and Repair” and the Centre National de la Recherche Scientifique. We also acknowledge support from the European Commission under the Seventh Framework Programme (FP7), contract Bio-NMR 261863.
- Fändrich M, Schmidt M, Grigorieff N (2011) Recent progress in understanding Alzheimer’s β-amyloid structures. Trends Biochem Sci:1–8Google Scholar
- Irie K, Murakami K, Masuda Y, Morimoto A, Ohigashi H, Ohashi R, Takegoshi K, Nagao M, Shimizu T, Shirasawa T (2005) Structure of beta-amyloid fibrils and its relevance to their neurotoxicity: implications for the pathogenesis of Alzheimer’s disease. J Biosci Bioeng 99(5):437–447CrossRefGoogle Scholar