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

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

doi:10.1093/protein/gzm054

Journal Article

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

Wiesehan, K.FZJ* ; Stöhr, J. ; Nagel-Steger, K. ; van Groen, T. ; Riesner, D. ; Willbold, D.FZJ*

2008
Oxford Univ. Press Oxford

Protein engineering design and selection 21, 241 - 246 (2008) [10.1093/protein/gzm054]

This record in other databases:

Please use a persistent id in citations: http://hdl.handle.net/2128/25408 doi:10.1093/protein/gzm054

Abstract: 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.

Keyword(s): Amyloid beta-Peptides: antagonists & inhibitors (MeSH) ; Amyloid beta-Peptides: metabolism (MeSH) ; Amyloid beta-Peptides: toxicity (MeSH) ; Animals (MeSH) ; Cell Death: drug effects (MeSH) ; Cytotoxins: antagonists & inhibitors (MeSH) ; Cytotoxins: metabolism (MeSH) ; Cytotoxins: toxicity (MeSH) ; Microscopy, Electron (MeSH) ; PC12 Cells (MeSH) ; Peptides: chemistry (MeSH) ; Peptides: metabolism (MeSH) ; Peptides: pharmacology (MeSH) ; Polymers: metabolism (MeSH) ; Protein Binding (MeSH) ; Protein Structure, Secondary: drug effects (MeSH) ; Rats (MeSH) ; Spectrometry, Fluorescence (MeSH) ; Substrate Specificity (MeSH) ; Thiazoles: metabolism (MeSH) ; Amyloid beta-Peptides ; Cytotoxins ; Peptides ; Polymers ; Thiazoles ; thioflavin T ; J ; A beta (auto) ; aggregation (auto) ; Alzheimer's disease (auto) ; cytotoxicity (auto) ; D-amino acid peptide (auto)