Ligand-induced flocculation of neurotoxic fibrillar Abeta(1-42) by noncovalent crosslinking.
Aggregation of the amyloid-beta (Abeta) peptides has a pivotal role in Alzheimer's disease (AD). Small molecules and short peptides/peptidomimetics can exert their full protective effects against Abeta 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 Abeta(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. zeta-Potential measurements revealed a slightly increased electrostatic stability of the Abeta 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 Abeta fibrils can explain the neuroprotective effects.
Hetényi
Anasztázia
A
Institute of Pharmaceutical Chemistry, University of Szeged, Eötvös u. 6, 6720 Szeged, Hungary.
Fülöp
Lívia
L
Martinek
Tamás A
TA
Wéber
Edit
E
Soós
Katalin
K
Penke
Botond
B
D016229:Amyloid beta-Peptides / Q000737:chemistry*; D052160:Benzothiazoles; D001665:Binding Sites; D005427:Flocculation; D008024:Ligands; D009682:Magnetic Resonance Spectroscopy / Q000379:methods / Q000592:standards; D046529:Microscopy, Electron, Transmission / Q000379:methods; D010316:Particle Size; D010446:Peptide Fragments / Q000737:chemistry*; D010455:Peptides / Q000737:chemistry*; D012015:Reference Standards; D013499:Surface Properties; D013844:Thiazoles / Q000737:chemistry*; D013997:Time Factors
D016229:Amyloid beta-Peptides; D052160:Benzothiazoles; D008024:Ligands; D010446:Peptide Fragments; D010455:Peptides; D013844:Thiazoles; C075222:amyloid beta-protein (1-42); C009462:thioflavin T