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. © The Author 2008. Published by Oxford University Press. All rights reserved.