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Ligand‐Induced Flocculation of Neurotoxic Fibrillar Aβ(1–42) by Noncovalent Crosslinking
Author(s) -
Hetényi Anasztázia,
Fülöp Lívia,
Martinek Tamás A.,
Wéber Edit,
Soós Katalin,
Penke Botond
Publication year - 2008
Publication title -
chembiochem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.05
H-Index - 126
eISSN - 1439-7633
pISSN - 1439-4227
DOI - 10.1002/cbic.200700351
Subject(s) - biophysics , chemistry , ligand (biochemistry) , fibril , amyloid (mycology) , peptide , biochemistry , receptor , biology , inorganic chemistry
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.