TY  - JOUR
AU  - Wiesehan, K.
AU  - Stöhr, J.
AU  - Nagel-Steger, K.
AU  - van Groen, T.
AU  - Riesner, D.
AU  - Willbold, D.
TI  - Inhibition of cytotoxicity and amyloid fibril formation by a D-amino acid peptide that specifically binds to Alzheimer's disease amyloid peptide
JO  - Protein engineering design and selection
VL  - 21
SN  - 1741-0126
CY  - Oxford
PB  - Oxford Univ. Press
M1  - PreJuSER-338
SP  - 241 - 246
PY  - 2008
N1  - Record converted from VDB: 12.11.2012
AB  - 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.
KW  - Amyloid beta-Peptides: antagonists & inhibitors
KW  - Amyloid beta-Peptides: metabolism
KW  - Amyloid beta-Peptides: toxicity
KW  - Animals
KW  - Cell Death: drug effects
KW  - Cytotoxins: antagonists & inhibitors
KW  - Cytotoxins: metabolism
KW  - Cytotoxins: toxicity
KW  - Microscopy, Electron
KW  - PC12 Cells
KW  - Peptides: chemistry
KW  - Peptides: metabolism
KW  - Peptides: pharmacology
KW  - Polymers: metabolism
KW  - Protein Binding
KW  - Protein Structure, Secondary: drug effects
KW  - Rats
KW  - Spectrometry, Fluorescence
KW  - Substrate Specificity
KW  - Thiazoles: metabolism
KW  - Amyloid beta-Peptides (NLM Chemicals)
KW  - Cytotoxins (NLM Chemicals)
KW  - Peptides (NLM Chemicals)
KW  - Polymers (NLM Chemicals)
KW  - Thiazoles (NLM Chemicals)
KW  - thioflavin T (NLM Chemicals)
KW  - J (WoSType)
LB  - PUB:(DE-HGF)16
C6  - pmid:18252750
UR  - <Go to ISI:>//WOS:000254295200003
DO  - DOI:10.1093/protein/gzm054
UR  - https://juser.fz-juelich.de/record/338
ER  -