title: Branched KLVFF tetramers strongly potentiate inhibition of beta-amyloid aggregation.
abstract: The key pathogenic event in the onset of Alzheimer's disease (AD) is the aggregation of beta-amyloid (Abeta) peptides into toxic aggregates. Molecules that interfere with this process might act as therapeutic agents for the treatment of AD. The amino acid residues 16-20 (KLVFF) are known to be essential for the aggregation of Abeta. In this study, we have used a first-generation dendrimer as a scaffold for the multivalent display of the KLVFF peptide. The effect of four KLVFF peptides attached to the dendrimer (K(4)) on Abeta aggregation was compared to the effect of monomeric KLVFF (K(1)). Our data show that K(4) very effectively inhibits the aggregation of low-molecular-weight and protofibrillar Abeta(1-42) into fibrils, in a concentration-dependent manner, and much more potently than K(1). Moreover, we show that K(4) can lead to the disassembly of existing aggregates. Our data lead us to propose that conjugates that bear multiple copies of KLVFF might be useful as therapeutic agents for the treatment of Alzheimer's disease.
authors.affiliation: Neurogenetics Laboratory, Academic Medical Center, P.O. Box 22660, 1100 DD Amsterdam, The Netherlands.
authors.forename: Sidhartha M
authors.initials: SM
authors.lastname: Chafekar
authors.forename: Hinke
authors.initials: H
authors.lastname: Malda
authors.forename: Maarten
authors.initials: M
authors.lastname: Merkx
authors.forename: E W
authors.initials: EW
authors.lastname: Meijer
authors.forename: David
authors.initials: D
authors.lastname: Viertl
authors.forename: Hilal A
authors.initials: HA
authors.lastname: Lashuel
authors.forename: Frank
authors.initials: F
authors.lastname: Baas
authors.forename: Wiep
authors.initials: W
authors.lastname: Scheper
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy* / Q000473:pathology; D000595:Amino Acid Sequence; D000682:Amyloid / Q000737:chemistry / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000378:metabolism; D050091:Dendrimers / Q000737:chemistry / Q000494:pharmacology; D018625:Microscopy, Atomic Force; D008969:Molecular Sequence Data; D008970:Molecular Weight; D009842:Oligopeptides / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D000682:Amyloid; D016229:Amyloid beta-Peptides; D050091:Dendrimers; C478940:Lys-Leu-Val-Phe-Phe-Lys-Lys-Lys-Lys-Lys-Lys; D009842:Oligopeptides