Ligand-Induced Flocculation of Neurotoxic Fibrillar Abeta(1-42) by Noncovalent Crosslinking

Hetényi, Anasztázia and Fülöp, Lívia and Martinek, Tamás and Wéber, Edit and Soós, Katalin and Penke, Botond (2008) Ligand-Induced Flocculation of Neurotoxic Fibrillar Abeta(1-42) by Noncovalent Crosslinking. CHEMBIOCHEM, 9 (5). pp. 748-757. ISSN 1439-4227

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Abstract

Aggregation of the amyloid- (A) peptides has a pivotal role in Alzheimers disease (AD). Small molecules and short peptides/peptidomimetics can exert their full protective effects against A 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 A(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. -Potential measurements revealed a slightly increased electrostatic stability of the A 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 A fibrils can explain the neuroprotective effects.

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