title: Sulindac Sulfide Induces the Formation of Large Oligomeric Aggregates of the Alzheimer's Disease Amyloid-β Peptide Which Exhibit Reduced Neurotoxicity.
abstract: 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. (13)C-(19)F transferred echo double resonance experiments suggest that sulindac sulfide colocalizes with the Aβ peptide in the aggregate.
authors.affiliation: Munich Center for Integrated Protein Science (CIPS-M) at Department Chemie, Technische Universität München (TUM) , Lichtenbergstrasse 4, 85747 Garching, Germany.
authors.forename: Elke
authors.initials: E
authors.lastname: Prade
authors.affiliation: Department of Pharmacology & Therapeutics, McGill University , 3655 Promenade Sir-William-Osler, Montreal, Quebec H3G 1Y6, Canada.
authors.forename: Christian
authors.initials: C
authors.lastname: Barucker
authors.affiliation: Munich Center for Integrated Protein Science (CIPS-M) at Department Chemie, Technische Universität München (TUM) , Lichtenbergstrasse 4, 85747 Garching, Germany.
authors.forename: Riddhiman
authors.initials: R
authors.lastname: Sarkar
authors.affiliation: Bruker BioSpin, Silberstreifen 4, 76287 Rheinstetten, Germany.
authors.forename: Gerhard
authors.initials: G
authors.lastname: Althoff-Ospelt
authors.affiliation: Leibniz-Institut für Molekulare Pharmakologie (FMP), Robert-Rössle-Strasse 10, 13125 Berlin, Germany.
authors.forename: Juan Miguel
authors.initials: JM
authors.lastname: Lopez del Amo
authors.affiliation: Department of Pharmacology & Therapeutics, McGill University , 3655 Promenade Sir-William-Osler, Montreal, Quebec H3G 1Y6, Canada.
authors.forename: Shireen
authors.initials: S
authors.lastname: Hossain
authors.affiliation: Department of Pharmacology & Therapeutics, McGill University , 3655 Promenade Sir-William-Osler, Montreal, Quebec H3G 1Y6, Canada.
authors.forename: Yifei
authors.initials: Y
authors.lastname: Zhong
authors.affiliation: Department of Pharmacology & Therapeutics, McGill University , 3655 Promenade Sir-William-Osler, Montreal, Quebec H3G 1Y6, Canada.
authors.forename: Gerd
authors.initials: G
authors.lastname: Multhaup
authors.affiliation: Munich Center for Integrated Protein Science (CIPS-M) at Department Chemie, Technische Universität München (TUM) , Lichtenbergstrasse 4, 85747 Garching, Germany.|Helmholtz-Zentrum München (HMGU), Deutsches Forschungszentrum für Gesundheit und Umwelt, Ingolstädter Landstrasse 1, 85764 Neuherberg, Germany.
authors.forename: Bernd
authors.initials: B
authors.lastname: Reif
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism*; D000595:Amino Acid Sequence; D016229:Amyloid beta-Peptides / Q000378:metabolism* / Q000633:toxicity; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000378:metabolism* / Q000633:toxicity; D066329:Protein Aggregates / Q000187:drug effects / Q000502:physiology*; D013467:Sulindac / Q000031:analogs & derivatives* / Q000494:pharmacology
chemical_list: D016229:Amyloid beta-Peptides; D000894:Anti-Inflammatory Agents, Non-Steroidal; D010446:Peptide Fragments; D066329:Protein Aggregates; C078592:amyloid beta-protein (1-40); C075222:amyloid beta-protein (1-42); D013467:Sulindac; C025462:sulindac sulfide