Sulindac Sulfide Induces the Formation of Large Oligomeric Aggregates of the Alzheimer’s Disease Amyloid‑β Peptide Which Exhibit Reduced Neurotoxicity

• Published in: Biochemistry (Easton) Vol. 55; no. 12; pp. 1839 - 1849
• Main Authors: Prade, Elke, Barucker, Christian, Sarkar, Riddhiman, Althoff-Ospelt, Gerhard, Lopez del Amo, Juan Miguel, Hossain, Shireen, Zhong, Yifei, Multhaup, Gerd, Reif, Bernd
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 29.03.2016
• Subjects: Alzheimer Disease - metabolism; Amino Acid Sequence; Amyloid beta-Peptides - metabolism; Amyloid beta-Peptides - toxicity; Anti-Inflammatory Agents, Non-Steroidal - pharmacology; Cell Line, Tumor; Dose-Response Relationship, Drug; Humans; Molecular Sequence Data; Peptide Fragments - metabolism; Peptide Fragments - toxicity; Protein Aggregates - drug effects; Protein Aggregates - physiology; Sulindac - analogs & derivatives; Sulindac - pharmacology
• ISSN: 0006-2960; 1520-4995
• DOI: 10.1021/acs.biochem.5b01272

Alzheimer’s disease is characterized by deposition of the amyloid β-peptide (Aβ) 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 Aβ 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 Aβ solution. We find that sulindac sulfide induced Aβ aggregates are structurally homogeneous. The C-terminal part of the peptide adopts a β-sheet structure, whereas the N-terminus is disordered. The salt bridge between D23 and K28 is present, similar as in wild type fibril structures. 13C–19F transferred echo double resonance experiments suggest that sulindac sulfide colocalizes with the Aβ peptide in the aggregate.