Sulindac Sulfide Induces the Formation of Large Oligomeric Aggregates of the Alzheimer's Disease Amyloid-beta Peptide Which Exhibit Reduced Neurotoxicity

摘要

Alzheimer's disease is characterized by deposition of the amyloid beta-peptide (A beta) in brain tissue of affected individuals. In recent years, many potential lead structures have been suggested that can potentially be used for diagnosis and therapy. However, the mode of action of these compounds is so far not understood. Among these small molecules, the nonsteroidal anti-inflammatory drug (NSAID) sulindac sulfide received a lot of attention. In this manuscript, we characterize the interaction between the monomeric A beta peptide and the NSAID sulindac sulfide. We find that sulindac sulfide efficiently depletes the pool of toxic oligomers by enhancing the rate of fibril formation. In vitro, sulindac sulfide forms colloidal particles which catalyze the formation of fibrils. Aggregation is immediate, presumably by perturbing the supersaturated A beta solution. We find that sulindac sulfide induced A beta aggregates are structurally homogeneous. The C-terminal part of the peptide adopts a beta-sheet structure, whereas the N-tetminus is disordered. The salt bridge between D23 and K28 is present, similar as in wild type fibril structures. C-13-F-19 transferred echo double resonance experiments suggest that sulindac sulfide colocalizes with the A beta peptide in the aggregate.