Branched KLVFF tetramers strongly potentiate inhibition of β-amyloid aggregation

Sidhartha M. Chafekar, Hinke Malda, Maarten Merkx, E. W. Meijer, David Viertl, Hilal A. Lashuel, Frank Baas, Wiep Scheper

Research output: Contribution to journalArticle

89 Citations (Scopus)

Abstract

The key pathogenic event in the onset of Alzheimer's disease (AD) is the aggregation of β-amyloid (Aβ) 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 Aβ. 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 (K4) on Aβ aggregation was compared to the effect of monomeric KLVFF (K1). Our data show that K4 very effectively inhibits the aggregation of low-molecular-weight and protofibriliar Aβ1-42, into fibrils, in a concentration-dependent manner, and much more potently than K1. Moreover, we show that K4 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.

Original languageEnglish
Pages (from-to)1857-1864
Number of pages8
JournalChemBioChem
Volume8
Issue number15
DOIs
Publication statusPublished - 15 Oct 2007
Externally publishedYes

Fingerprint

Amyloid
Agglomeration
Dendrimers
Alzheimer Disease
Peptides
Poisons
Therapeutics
Scaffolds
Molecular Weight
Molecular weight
Display devices
amyloid beta-protein (16-20)
Inhibition (Psychology)
Amino Acids
Molecules

Keywords

  • Aggregation inhibitors
  • Alzheimer's disease
  • Beta-amyloid peptides
  • Dendrimers
  • Multivalency
  • Neurochemistry

ASJC Scopus subject areas

  • Drug Discovery
  • Organic Chemistry
  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Chafekar, S. M., Malda, H., Merkx, M., Meijer, E. W., Viertl, D., Lashuel, H. A., ... Scheper, W. (2007). Branched KLVFF tetramers strongly potentiate inhibition of β-amyloid aggregation. ChemBioChem, 8(15), 1857-1864. https://doi.org/10.1002/cbic.200700338

Branched KLVFF tetramers strongly potentiate inhibition of β-amyloid aggregation. / Chafekar, Sidhartha M.; Malda, Hinke; Merkx, Maarten; Meijer, E. W.; Viertl, David; Lashuel, Hilal A.; Baas, Frank; Scheper, Wiep.

In: ChemBioChem, Vol. 8, No. 15, 15.10.2007, p. 1857-1864.

Research output: Contribution to journalArticle

Chafekar, SM, Malda, H, Merkx, M, Meijer, EW, Viertl, D, Lashuel, HA, Baas, F & Scheper, W 2007, 'Branched KLVFF tetramers strongly potentiate inhibition of β-amyloid aggregation', ChemBioChem, vol. 8, no. 15, pp. 1857-1864. https://doi.org/10.1002/cbic.200700338
Chafekar SM, Malda H, Merkx M, Meijer EW, Viertl D, Lashuel HA et al. Branched KLVFF tetramers strongly potentiate inhibition of β-amyloid aggregation. ChemBioChem. 2007 Oct 15;8(15):1857-1864. https://doi.org/10.1002/cbic.200700338
Chafekar, Sidhartha M. ; Malda, Hinke ; Merkx, Maarten ; Meijer, E. W. ; Viertl, David ; Lashuel, Hilal A. ; Baas, Frank ; Scheper, Wiep. / Branched KLVFF tetramers strongly potentiate inhibition of β-amyloid aggregation. In: ChemBioChem. 2007 ; Vol. 8, No. 15. pp. 1857-1864.
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