Inhibition of cytotoxicity and amyloid fibril formation by a D-amino acid peptide that specifically binds to Alzheimer's disease amyloid peptide.
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.
Wiesehan
K
K
Forschungszentrum Jülich, IBI-2, 52425 Jülich, Germany.
Stöhr
J
J
Nagel-Steger
L
L
van Groen
T
T
Riesner
D
D
Willbold
D
D
D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors* / Q000378:metabolism* / Q000633:toxicity; D000818:Animals; D052160:Benzothiazoles; D016923:Cell Death / Q000187:drug effects; D003603:Cytotoxins / Q000037:antagonists & inhibitors* / Q000378:metabolism / Q000633:toxicity; D008854:Microscopy, Electron; D016716:PC12 Cells; D010455:Peptides / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D011108:Polymers / Q000378:metabolism; D011485:Protein Binding; D017433:Protein Structure, Secondary / Q000187:drug effects; D051381:Rats; D013050:Spectrometry, Fluorescence; D013379:Substrate Specificity; D013844:Thiazoles / Q000378:metabolism
D016229:Amyloid beta-Peptides; D052160:Benzothiazoles; D003603:Cytotoxins; D010455:Peptides; D011108:Polymers; D013844:Thiazoles; C009462:thioflavin T