[NMR paper] Structural analysis of the pyroglutamate-modified isoform of the Alzheimer's disease-related amyloid-? using NMR spectroscopy.

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

Related Articles Structural analysis of the pyroglutamate-modified isoform of the Alzheimer's disease-related amyloid-? using NMR spectroscopy.

J Pept Sci. 2012 Nov;18(11):691-5

Authors: Sun N, Hartmann R, Lecher J, Stoldt M, Funke SA, Gremer L, Ludwig HH, Demuth HU, Kleinschmidt M, Willbold D

Abstract
The aggregation of the A? plays a fundamental role in the pathology of AD. Recently, N-terminally modified A? species, pE-A?, have been described as major constituents of A? deposits in the brains of AD patients. pE-A? has an increased aggregation propensity and shows increased toxicity compared with A?1-40 and A?1-42. In the present work, high-resolution NMR spectroscopy was performed to study pE-A?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?3-40 was shown to contain two helical regions formed by residues 14-22 and 30-36. This is similar as previously described for A?1-40. However, the secondary chemical shift data indicate decreased helical propensity in pE-A?3-40 when compared with A?1-40 under exactly the same conditions. This is in agreement with the observation that pE-A?3-40 shows a drastically increased tendency to form ?-sheet-rich structures under more physiologic conditions. Structural studies of pE-A? 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? for the pathogenesis of AD.


PMID: 23001756 [PubMed - indexed for MEDLINE]



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