Solid-phase synthesis and characterization of N-terminally elongated A 
beta(-3-x)-peptides.

Beyer, I.; Rezaei-Ghaleh, N.; Klafki, H. W.; Jahn, O.; Haussmann, U.; Wiltfang, J.; Zweckstetter, M.; Knölker, H. J.

doi:10.1002/chem.201600892

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Solid-phase synthesis and characterization of N-terminally elongated A beta(-3-x)-peptides.

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Rezaei-Ghaleh, N.
Research Group of Protein Strcture Determination using NMR, MPI for biophysical chemistry, Max Planck Society;

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Zweckstetter, M.
Research Group of Protein Strcture Determination using NMR, MPI for biophysical chemistry, Max Planck Society;

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Citation

Beyer, I., Rezaei-Ghaleh, N., Klafki, H. W., Jahn, O., Haussmann, U., Wiltfang, J., et al. (2016). Solid-phase synthesis and characterization of N-terminally elongated A beta(-3-x)-peptides. Chemistry-A European Journal, 22(25), 8685-8693. doi:10.1002/chem.201600892.

Cite as: https://hdl.handle.net/11858/00-001M-0000-002B-300D-7

Abstract

In addition to the prototypic amyloid-beta (A beta) peptides A beta(1-40) and A beta(1-42), several A beta variants differing in their amino and carboxy termini have been described. Synthetic availability of an A beta variant is often the key to study its role under physiological or pathological conditions. Herein, we report a protocol for the efficient solid-phase peptide synthesis of the N-terminally elongated Ab-peptides A beta(-3-38), A beta(-3-40), and A beta(-3-42). Biophysical characterization by NMR spectroscopy, CD spectroscopy, an aggregation assay, and electron microscopy revealed that all three peptides were prone to aggregation into amyloid fibrils. Immunoprecipitation, followed by mass spectrometry, indicated that A beta(-3-38) and A beta(-3-40) are generated by transfected cells even in the presence of a tripartite beta-site amyloid precursor protein cleaving enzyme 1 (BACE1) inhibitor. The elongated Ab peptides starting at Val(-3) can be separated from N-terminally-truncated A beta forms by high-resolution isoelectric-focusing techniques, despite virtually identical isoelectric points. The synthetic A beta variants and the methods presented here are providing tools to advance our understanding of the potential roles of N-terminally elongated A beta variants in Alzheimer's disease.