Branched KLVFF tetramers strongly potentiate inhibition of beta-amyloid aggregation

Branched KLVFF tetramers strongly potentiate inhibition of beta-amyloid aggregation. Chafekar, S. M, Malda, H., Merkx, M., Meijer, E W, Viertl, D., Lashuel, H. A, Baas, F., & Scheper, W. Chembiochem, 8(15):1857–1864, Germany, October, 2007.
abstract bibtex

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.

@ARTICLE{Chafekar2007-bh,
  title    = "Branched {KLVFF} tetramers strongly potentiate inhibition of
              beta-amyloid aggregation",
  author   = "Chafekar, Sidhartha M and Malda, Hinke and Merkx, Maarten and
              Meijer, E W and Viertl, David and Lashuel, Hilal A and Baas,
              Frank and Scheper, Wiep",
  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.",
  journal  = "Chembiochem",
  volume   =  8,
  number   =  15,
  pages    = "1857--1864",
  month    =  oct,
  year     =  2007,
  address  = "Germany",
  language = "en"
}

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