0000000000354466

AUTHOR

Thomas B. Ladd

showing 3 related works from this author

Inhibitors of Rho-kinase modulate amyloid-β (Aβ) secretion but lack selectivity for Aβ42

2005

Certain non-steroidal anti-inflammatory drugs (NSAIDs) preferentially inhibit production of the amyloidogenic Abeta42 peptide, presumably by direct modulation of gamma-secretase activity. A recent report indicated that NSAIDs could reduce Abeta42 by inhibition of the small GTPase Rho, and a single inhibitor of Rho kinase (ROCK) mimicked the effects of Abeta42-lowering NSAIDs. To investigate whether Abeta42 reduction is a common property of ROCK inhibitors, we tested commercially available compounds in cell lines that were previously used to demonstrate the Abeta42-lowering activity of NSAIDs. Surprisingly, we found that two ROCK inhibitors reduced total Abeta secretion in a dose-dependent m…

Cell SurvivalMutantPeptideCHO CellsProtein Serine-Threonine KinasesPharmacologyBiochemistryAmyloid beta-Protein PrecursorCellular and Molecular NeuroscienceCricetulusCricetinaeEndopeptidasesmental disordersAmyloid precursor proteinAnimalsAspartic Acid EndopeptidasesSecretionSmall GTPaseEnzyme InhibitorsRho-associated protein kinasechemistry.chemical_classificationrho-Associated KinasesAmyloid beta-PeptidesbiologyAnti-Inflammatory Agents Non-SteroidalIntracellular Signaling Peptides and ProteinsIn vitro toxicologyProtein-Tyrosine KinasesPeptide Fragmentsnervous system diseasesBiochemistrychemistrybiology.proteinAmyloid Precursor Protein SecretasesSelectivityProtein Processing Post-TranslationalJournal of Neurochemistry
researchProduct

Independent Generation of Aβ42 and Aβ38 Peptide Species by γ-Secretase

2008

Proteolytic processing of the amyloid precursor protein by beta- and gamma-secretase generates the amyloid-beta (Abeta) peptides, which are principal drug targets in Alzheimer disease therapeutics. gamma-Secretase has imprecise cleavage specificity and generates the most abundant Abeta40 and Abeta42 species together with longer and shorter peptides such as Abeta38. Several mechanisms could explain the production of multiple Abeta peptides by gamma-secretase, including sequential processing of longer into shorter Abeta peptides. A novel class of gamma-secretase modulators (GSMs) that includes some non-steroidal anti-inflammatory drugs has been shown to selectively lower Abeta42 levels withou…

chemistry.chemical_classificationGel electrophoresisbiologyChinese hamster ovary cellMedizinWild typePeptideCell BiologyCleavage (embryo)biology.organism_classificationBiochemistrynervous system diseasesBiochemistrychemistrymental disordersAmyloid precursor proteinbiology.proteinCricetulusMolecular BiologyPeptide sequenceJournal of Biological Chemistry
researchProduct

Diverse compounds mimic Alzheimer disease–causing mutations by augmenting Aβ42 production

2004

Increased Abeta42 production has been linked to the development of Alzheimer disease. We now identify a number of compounds that raise Abeta42. Among the more potent Abeta42-raising agents identified are fenofibrate, an antilipidemic agent, and celecoxib, a COX-2-selective NSAID. Many COX-2-selective NSAIDs tested raised Abeta42, including multiple COX-2-selective derivatives of two Abeta42-lowering NSAIDs. Compounds devoid of COX activity and the endogenous isoprenoids FPP and GGPP also raised Abeta42. These compounds seem to target the gamma-secretase complex, increasing gamma-secretase-catalyzed production of Abeta42 in vitro. Short-term in vivo studies show that two Abeta42-raising comp…

Enzyme-Linked Immunosorbent AssayEndogenyProtein Serine-Threonine KinasesPharmacologyTransfectionMass SpectrometryGeneral Biochemistry Genetics and Molecular BiologyPresenilinCell LineFenofibrateAlzheimer DiseaseIn vivoEndopeptidasesmedicineAspartic Acid EndopeptidasesHumansImmunoprecipitationCyclooxygenase InhibitorsProtein precursorHypolipidemic AgentsSulfonamidesrho-Associated KinasesAmyloid beta-PeptidesFenofibratebusiness.industryAnti-Inflammatory Agents Non-SteroidalIntracellular Signaling Peptides and ProteinsBrainGeneral Medicinemedicine.diseaseIn vitroEnzyme ActivationBiochemistryCelecoxibPyrazolesFemaleAmyloid Precursor Protein SecretasesAlzheimer's diseaserhoA GTP-Binding ProteinbusinessAntilipidemic Agentmedicine.drugNature Medicine
researchProduct