title: Second generation γ-secretase modulators exhibit different modulation of Notch β and Aβ production.
abstract: The γ-secretase complex is an appealing drug target when the therapeutic strategy is to alter amyloid-β peptide (Aβ) aggregation in Alzheimer disease. γ-Secretase is directly involved in Aβ formation and determines the pathogenic potential of Aβ by generating the aggregation-prone Aβ42 peptide. Because γ-secretase mediates cleavage of many substrates involved in cell signaling, such as the Notch receptor, it is crucial to sustain these pathways while altering the Aβ secretion. A way of avoiding interference with the physiological function of γ-secretase is to use γ-secretase modulators (GSMs) instead of inhibitors of the enzyme. GSMs modify the Aβ formation from producing the amyloid-prone Aβ42 variant to shorter and less amyloidogenic Aβ species. The modes of action of GSMs are not fully understood, and even though the pharmacology of GSMs has been thoroughly studied regarding Aβ generation, knowledge is lacking about their effects on other substrates, such as Notch. Here, using immunoprecipitation followed by MALDI-TOF MS analysis, we found that two novel, second generation GSMs modulate both Notch β and Aβ production. Moreover, by correlating S3-specific Val-1744 cleavage of Notch intracellular domain (Notch intracellular domain) to total Notch intracellular domain levels using immunocytochemistry, we also demonstrated that Notch intracellular domain is not modulated by the compounds. Interestingly, two well characterized, nonsteroidal anti-inflammatory drugs (nonsteroidal anti-inflammatory drug), R-flurbiprofen and sulindac sulfide, affect only Aβ and not Notch β formation, indicating that second generation GSMs and nonsteroidal anti-inflammatory drug-based GSMs have different modes of action regarding Notch processing.
authors.affiliation: Department of Neurobiology, Care Sciences and society, KI-Alzheimer's Disease Research Center, Karolinska Institutet, 14157 Stockholm, Sweden.
authors.forename: Johanna
authors.initials: J
authors.lastname: Wanngren
authors.forename: Jan
authors.initials: J
authors.lastname: Ottervald
authors.forename: Santiago
authors.initials: S
authors.lastname: Parpal
authors.forename: Erik
authors.initials: E
authors.lastname: Portelius
authors.forename: Kia
authors.initials: K
authors.lastname: Strömberg
authors.forename: Tomas
authors.initials: T
authors.lastname: Borgegård
authors.forename: Rebecka
authors.initials: R
authors.lastname: Klintenberg
authors.forename: Anders
authors.initials: A
authors.lastname: Juréus
authors.forename: Jenny
authors.initials: J
authors.lastname: Blomqvist
authors.forename: Kaj
authors.initials: K
authors.lastname: Blennow
authors.forename: Henrik
authors.initials: H
authors.lastname: Zetterberg
authors.forename: Johan
authors.initials: J
authors.lastname: Lundkvist
authors.forename: Susanne
authors.initials: S
authors.lastname: Rosqvist
authors.forename: Helena
authors.initials: H
authors.lastname: Karlström
mesh_terms: D000682:Amyloid / Q000235:genetics / Q000378:metabolism*; D053829:Amyloid Precursor Protein Secretases / Q000235:genetics / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D005260:Female; D005480:Flurbiprofen / Q000494:pharmacology*; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D011499:Protein Processing, Post-Translational / Q000187:drug effects / Q000235:genetics; D017434:Protein Structure, Tertiary; D051880:Receptors, Notch / Q000235:genetics / Q000378:metabolism*; D013467:Sulindac / Q000031:analogs & derivatives* / Q000494:pharmacology
chemical_list: C545487:APP protein, human; D000682:Amyloid; D016564:Amyloid beta-Protein Precursor; D000894:Anti-Inflammatory Agents, Non-Steroidal; D051880:Receptors, Notch; D013467:Sulindac; D005480:Flurbiprofen; C025462:sulindac sulfide; D053829:Amyloid Precursor Protein Secretases