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PEDS Advance Access originally published online on February 5, 2008
Protein Engineering Design and Selection 2008 21(4):241-246; doi:10.1093/protein/gzm054
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© The Author 2008. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org

Inhibition of cytotoxicity and amyloid fibril formation by a D-amino acid peptide that specifically binds to Alzheimer’s disease amyloid peptide

K. Wiesehan1, J. Stöhr2, L. Nagel-Steger2, T. van Groen3, D. Riesner2 and D. Willbold1,2,4

1Forschungszentrum Jülich, IBI-2, 52425 Jülich, Germany 2 Institut für Physikalische Biologie, BMFZ, Heinrich-Heine-Universität, 40225 Düsseldorf, Germany 3Department of Cell Biology, University of Alabama at Birmingham, Birmingham, AL 35294, USA

4 To whom correspondence should be addressed. E-mail: dieter.willbold{at}uni-duesseldorf.de, d.willbold{at}fz-juelich.de

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder. The ‘amyloid cascade hypothesis’ assigns the amyloid-beta-peptide (Aβ) a central role in the pathogenesis of AD. Although it is not yet established, whether the resulting Aβ aggregates are the causative agent or just a result of the disease progression, polymerization of Aβ has been identified as a major feature during AD pathogenesis. Inhibition of the Aβ polymer formation, thus, has emerged as a potential therapeutic approach. In this context, we identified peptides consisting of D-enantiomeric amino acid peptides (D-peptides) that bind to Aβ. D-peptides are known to be more protease resistant and less immunogenic than the respective L-enantiomers. Previously, we have shown that a 12mer D-peptide specifically binds to Aβ amyloid plaques in brain tissue sections from former AD patients. In vitro obtained binding affinities to synthetic Aβ revealed a Kd value in the submicromolar range. The aim of the present study was to investigate the influence of this D-peptide to Aβ polymerization and toxicity. Using cell toxicity assays, thioflavin fluorescence, fluorescence correlation spectroscopy and electron microscopy, we found a significant effect of the D-peptide on both. Presence of D-peptides (Dpep) reduces the average size of Aβ aggregates, but increases their number. In addition, Aβ cytotoxicity on PC12 cells is reduced in the presence of Dpep.

Keywords: Aβ/aggregation/Alzheimer’s disease/cytotoxicity/D-amino acid peptide

Received April 22, 2007; revised September 14, 2007; accepted September 14, 2007.


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