Structural analysis of the pyroglutamate-modified isoform of the Alzheimer's disease-related amyloid-β using NMR spectroscopy

The aggregation of the A beta plays a fundamental role in the pathology of AD. Recently, N-terminally modified A beta species, pE-A beta, have been described as major constituents of A beta deposits in the brains of AD patients. pE-A beta has an increased aggregation propensity and shows increased toxicity compared with A beta 1-40 and A beta 1-42. In the present work, high-resolution NMR spectroscopy was performed to study pE-A beta 3-40 in aqueous TFE-containing solution. Two-dimensional TOCSY and NOESY experiments were performed. On the basis of NOE and chemical shift data, pE-A beta 3-40 was shown to contain two helical regions formed by residues 1422 and 3036. This is similar as previously described for A beta 1-40. However, the secondary chemical shift data indicate decreased helical propensity in pE-A beta 3-40 when compared with A beta 1-40 under exactly the same conditions. This is in agreement with the observation that pE-A beta 3-40 shows a drastically increased tendency to form beta-sheet-rich structures under more physiologic conditions. Structural studies of pE-A beta are crucial for better understanding the structural basis of amyloid fibril formation in the brain during development of AD, especially because an increasing number of reports indicate a decisive role of pE-A beta for the pathogenesis of AD. Copyright (c) 2012 European Peptide Society and John Wiley & Sons, Ltd.