title: Structural analysis of the pyroglutamate-modified isoform of the Alzheimer's disease-related amyloid-β using NMR spectroscopy.
abstract: The aggregation of the Aβ plays a fundamental role in the pathology of AD. Recently, N-terminally modified Aβ species, pE-Aβ, have been described as major constituents of Aβ deposits in the brains of AD patients. pE-Aβ has an increased aggregation propensity and shows increased toxicity compared with Aβ1-40 and Aβ1-42. In the present work, high-resolution NMR spectroscopy was performed to study pE-Aβ3-40 in aqueous TFE-containing solution. Two-dimensional TOCSY and NOESY experiments were performed. On the basis of NOE and chemical shift data, pE-Aβ3-40 was shown to contain two helical regions formed by residues 14-22 and 30-36. This is similar as previously described for Aβ1-40. However, the secondary chemical shift data indicate decreased helical propensity in pE-Aβ3-40 when compared with Aβ1-40 under exactly the same conditions. This is in agreement with the observation that pE-Aβ3-40 shows a drastically increased tendency to form β-sheet-rich structures under more physiologic conditions. Structural studies of pE-Aβ 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-Aβ for the pathogenesis of AD.
authors.affiliation: ICS-6, Forschungszentrum Jülich, 52425 Jülich, Germany.
authors.forename: Na
authors.initials: N
authors.lastname: Sun
authors.forename: Rudolf
authors.initials: R
authors.lastname: Hartmann
authors.forename: Justin
authors.initials: J
authors.lastname: Lecher
authors.forename: Matthias
authors.initials: M
authors.lastname: Stoldt
authors.forename: Susanne Aileen
authors.initials: SA
authors.lastname: Funke
authors.forename: Lothar
authors.initials: L
authors.lastname: Gremer
authors.forename: Hans-Henning
authors.initials: HH
authors.lastname: Ludwig
authors.forename: Hans-Ulrich
authors.initials: HU
authors.lastname: Demuth
authors.forename: Martin
authors.initials: M
authors.lastname: Kleinschmidt
authors.forename: Dieter
authors.initials: D
authors.lastname: Willbold
mesh_terms: D000544:Alzheimer Disease / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000737:chemistry*; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D020033:Protein Isoforms / Q000737:chemistry; D011761:Pyrrolidonecarboxylic Acid / Q000737:chemistry*
chemical_list: D016229:Amyloid beta-Peptides; D020033:Protein Isoforms; D011761:Pyrrolidonecarboxylic Acid