title: Sulindac sulfide is a noncompetitive gamma-secretase inhibitor that preferentially reduces Abeta 42 generation.
abstract: Nonsteroidal anti-inflammatory drugs (NSAIDs) have been known to reduce risk for Alzheimer's disease. In addition to the anti-inflammatory effects of NSAIDs to block cylooxygenase, it has been shown recently that a subset of NSAIDs selectively inhibits the secretion of highly amyloidogenic Abeta42 from cultured cells, although the molecular target(s) of NSAIDs in reducing the activity of gamma-secretase for Abeta42 generation (gamma(42)-secretase) still remain unknown. Here we show that sulindac sulfide (SSide) directly acts on gamma-secretase and preferentially inhibits the gamma(42)-secretase activity derived from the 3-[(3-cholamidopropyl)dimethylammonio]-2-hydroxy-1-propanesulfonate-solubilized membrane fractions of HeLa cells, in an in vitro gamma-secretase assay using recombinant amyloid beta precursor protein C100 as a substrate. SSide also inhibits activities for the generation of Abeta40 as well as for Notch intracellular domain at higher concentrations. Notably, SSide displayed linear noncompetitive inhibition profiles for gamma(42)-secretase in vitro. Our data suggest that SSide is a direct inhibitor of gamma-secretase that preferentially affects the gamma(42)-secretase activity.
authors.affiliation: Department of Neuropathology and Neuroscience, Graduate School of Pharmaceutical Sciences, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.
authors.forename: Yasuko
authors.initials: Y
authors.lastname: Takahashi
authors.forename: Ikuo
authors.initials: I
authors.lastname: Hayashi
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Tominari
authors.forename: Kentaro
authors.initials: K
authors.lastname: Rikimaru
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Morohashi
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Kan
authors.forename: Hideaki
authors.initials: H
authors.lastname: Natsugari
authors.forename: Tohru
authors.initials: T
authors.lastname: Fukuyama
authors.forename: Taisuke
authors.initials: T
authors.lastname: Tomita
authors.forename: Takeshi
authors.initials: T
authors.lastname: Iwatsubo
mesh_terms: D053829:Amyloid Precursor Protein Secretases; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D016282:Aspartic Acid Endopeptidases; D002478:Cells, Cultured; D018076:DNA, Complementary / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D010450:Endopeptidases / Q000378:metabolism*; D004797:Enzyme-Linked Immunosorbent Assay; D006367:HeLa Cells; D006801:Humans; D008565:Membrane Proteins / Q000378:metabolism; D009288:Naproxen / Q000494:pharmacology; D010446:Peptide Fragments / Q000378:metabolism*; D010455:Peptides / Q000737:chemistry; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D051880:Receptors, Notch; D013467:Sulindac / Q000031:analogs & derivatives* / Q000494:pharmacology*
chemical_list: D016229:Amyloid beta-Peptides; D000894:Anti-Inflammatory Agents, Non-Steroidal; D018076:DNA, Complementary; D008565:Membrane Proteins; D010446:Peptide Fragments; D010455:Peptides; D051880:Receptors, Notch; C075222:amyloid beta-protein (1-42); D013467:Sulindac; D009288:Naproxen; C025462:sulindac sulfide; D053829:Amyloid Precursor Protein Secretases; D010450:Endopeptidases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human