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Branched KLVFF Tetramers Strongly Potentiate Inhibition of β-Amyloid Aggregation

Authors

  • Sidhartha M. Chafekar,

    1. Neurogenetics Laboratory, Academic Medical Center, P. O. Box 22660, 1100 DD Amsterdam, The Netherlands, Fax: (+31 )20-5669312
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  • Hinke Malda,

    1. Department of Biomedical Engineering, Eindhoven University of Technology, P. O. Box 513, 5600 MB Eindhoven, The Netherlands, Fax: (+31)402451036
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  • Maarten Merkx,

    1. Department of Biomedical Engineering, Eindhoven University of Technology, P. O. Box 513, 5600 MB Eindhoven, The Netherlands, Fax: (+31)402451036
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  • E. W. Meijer,

    1. Department of Biomedical Engineering, Eindhoven University of Technology, P. O. Box 513, 5600 MB Eindhoven, The Netherlands, Fax: (+31)402451036
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  • David Viertl,

    1. Brain Mind Institute, Laboratory of Molecular Neurobiology and Neuroproteomics, Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland, Fax: (+41) 21-693-1780
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  • Hilal A. Lashuel,

    1. Brain Mind Institute, Laboratory of Molecular Neurobiology and Neuroproteomics, Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland, Fax: (+41) 21-693-1780
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  • Frank Baas,

    1. Neurogenetics Laboratory, Academic Medical Center, P. O. Box 22660, 1100 DD Amsterdam, The Netherlands, Fax: (+31 )20-5669312
    2. Department of Neurology, Academic Medical Center, University of Amsterdam, P. O. Box 22660, 1100 DD Amsterdam, The Netherlands, Fax: (+31) 205669312
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  • Wiep Scheper

    1. Neurogenetics Laboratory, Academic Medical Center, P. O. Box 22660, 1100 DD Amsterdam, The Netherlands, Fax: (+31 )20-5669312
    2. Department of Neurology, Academic Medical Center, University of Amsterdam, P. O. Box 22660, 1100 DD Amsterdam, The Netherlands, Fax: (+31) 205669312
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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 protofibrillar 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.

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