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

Aggregation of the amyloid-beta (A beta) peptides has a pivotal role in Alzheimer's disease (AD). Small molecules and short peptides/peptidomimetics can exert their full protective effects against A beta 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 beta(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 A beta 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 beta fibrils can explain the neuroprotective effects.