Ligand-induced flocculation of neurotoxic fibrillar aβ (1-42) by noncovalent crosslinking

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Abstract

Aggregation of the amyloid-β (Aβ) peptides has a pivotal role in Alzheimer's disease (AD). Small molecules and short peptides/ peptidomimetics can exert their full protective effects against Aβ within a short time-frame, but the exact mechanism of action is unclear. Time-dependent NMR spectroscopic binding and replacement experiments were carried out for peptide LPFFD and thioflavine T (ThT) on neurotoxic fibrillar Aβ(1-42), which revealed transient binding behavior for both compounds, and complex time-dependent features in the replacement experiments. The results of particle size measurements through the use of diffuse light-scattering and transmission electron microscopy support the conclusions that the studied ligands induced interfibrillar association on a short timescale, which explains the NMR spectroscopic binding and replacement results. ζ-Potential measurements revealed a slightly increased electrostatic stability of the Aβ fibrils upon ligand binding; this suggests that the interfibrillar assembly is driven by specific noncovalent cross-linking interactions. A specific surface and mobility decrease due to the ligand-induced flocculation of the Aβ fibrils can explain the neuroprotective effects.

Original languageEnglish
Pages (from-to)748-757
Number of pages10
JournalChemBioChem
Volume9
Issue number5
DOIs
Publication statusPublished - Mar 25 2008

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Keywords

  • Beta-amyloid peptides
  • Electron microscopy
  • NMR spectropy
  • Neurochemistry

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Organic Chemistry

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