A beta-amino acid modified heptapeptide containing a designed recognition element disrupts fibrillization of the amyloid beta-peptide.
We study the complex formation of a peptide betaAbetaAKLVFF, previously developed by our group, with Abeta(1-42) in aqueous solution. Circular dichroism spectroscopy is used to probe the interactions between betaAbetaAKLVFF and Abeta(1-42), and to study the secondary structure of the species in solution. Thioflavin T fluorescence spectroscopy shows that the population of fibers is higher in betaAbetaAKLVFF/Abeta(1-42) mixtures compared to pure Abeta(1-42) solutions. TEM and cryo-TEM demonstrate that co-incubation of betaAbetaAKLVFF with Abeta(1-42) causes the formation of extended dense networks of branched fibrils, very different from the straight fibrils observed for Abeta(1-42) alone. Neurotoxicity assays show that although betaAbetaAKLVFF alters the fibrillization of Abeta(1-42), it does not decrease the neurotoxicity, which suggests that toxic oligomeric Abeta(1-42) species are still present in the betaAbetaAKLVFF/Abeta(1-42) mixtures. Our results show that our designed peptide binds to Abeta(1-42) and changes the amyloid fibril morphology. This is shown to not necessarily translate into reduced toxicity.
Castelletto
Valeria
V
Department of Chemistry, The University of Reading, Reading RG6 6AD, UK. v.castelletto@reading.ac.uk
Hamley
Ian W
IW
Lim
Teck
T
De Tullio
Matias B
MB
Castaño
Eduardo M
EM
D000595:Amino Acid Sequence; D000682:Amyloid / Q000737:chemistry* / Q000187:drug effects; D016229:Amyloid beta-Peptides / Q000737:chemistry*; D000818:Animals; D052160:Benzothiazoles; D002942:Circular Dichroism; D020285:Cryoelectron Microscopy; D046529:Microscopy, Electron, Transmission; D009474:Neurons / Q000187:drug effects; D009498:Neurotoxins / Q000494:pharmacology; D009842:Oligopeptides / Q000737:chemistry* / Q000494:pharmacology / Q000633:toxicity; D010446:Peptide Fragments / Q000737:chemistry*; D017433:Protein Structure, Secondary; D051381:Rats; D013050:Spectrometry, Fluorescence; D013844:Thiazoles
D000682:Amyloid; D016229:Amyloid beta-Peptides; D052160:Benzothiazoles; D009498:Neurotoxins; D009842:Oligopeptides; D010446:Peptide Fragments; D013844:Thiazoles; C075222:amyloid beta-protein (1-42); C553733:beta-alanyl-beta-alanyl-lysyl-leucyl-valyl-phenylalanyl-phenylalanine; C009462:thioflavin T