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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. Since 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 mode 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 (Nβ) and Aβ production. Moreover, by correlating S3-specific V1744 cleavage of Notch intracellular domain (NICD) to total NICD levels using immunocytochemistry, we also demonstrated that NICD is not modulated by the compounds. Interestingly, two well characterized, non-steroidal anti-inflammatory drugs (NSAIDs), R-flurbiprofen and sulindac sulphide, affect only Aβ, and not Nβ formation, indicating that second-generation GSMs and NSAID-based GSMs have different modes of action regarding Notch processing.