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Wiesehan, K. [Author]; Stöhr, J. [Author]; Nagel-Steger, K. [Author]; van Groen, T. [Author]; Riesner, D. [Author]; Willbold, D. [Author]

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

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  • Media type: E-Article
  • Title: Inhibition of cytotoxicity and amyloid fibril formation by a D-amino acid peptide that specifically binds to Alzheimer's disease amyloid peptide
  • Contributor: Wiesehan, K. [Author]; Stöhr, J. [Author]; Nagel-Steger, K. [Author]; van Groen, T. [Author]; Riesner, D. [Author]; Willbold, D. [Author]
  • imprint: Oxford Univ. Press, 2008
  • Published in: Protein engineering design and selection 21, 241 - 246 (2008). doi:10.1093/protein/gzm054
  • Language: English
  • DOI: https://doi.org/10.1093/protein/gzm054
  • ISSN: 1741-0126
  • Keywords: A beta ; Cytotoxins: toxicity ; Protein Structure ; Secondary: drug effects ; Polymers: metabolism ; Amyloid beta-Peptides: toxicity ; Amyloid beta-Peptides ; aggregation ; cytotoxicity ; Fluorescence ; Rats ; PC12 Cells ; Spectrometry ; Animals ; Cytotoxins ; Protein Binding ; Electron ; D-amino acid peptide ; Thiazoles: metabolism ; Substrate Specificity ; Alzheimer's disease ; Peptides: metabolism ; Peptides: chemistry ; Polymers ; [...]
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  • Description: Alzheimer's disease (AD) is a progressive neurodegenerative disorder. The 'amyloid cascade hypothesis' assigns the amyloid-beta-peptide (Abeta) a central role in the pathogenesis of AD. Although it is not yet established, whether the resulting Abeta aggregates are the causative agent or just a result of the disease progression, polymerization of Abeta has been identified as a major feature during AD pathogenesis. Inhibition of the Abeta 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 Abeta. 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 Abeta amyloid plaques in brain tissue sections from former AD patients. In vitro obtained binding affinities to synthetic Abeta revealed a K(d) value in the submicromolar range. The aim of the present study was to investigate the influence of this d-peptide to Abeta 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 Abeta aggregates, but increases their number. In addition, Abeta cytotoxicity on PC12 cells is reduced in the presence of dpep.
  • Access State: Open Access