Specific Mutations in Aph1 Cause γ-Secretase Activation

Hikari Watanabe, Chika Yoshida, Masafumi Hidaka, Tomohisa Ogawa, Taisuke Tomita, Eugene Futai

    Research output: Contribution to journalArticlepeer-review

    1 Citation (Scopus)


    Amyloid beta peptides (Aβs) are generated from amyloid precursor protein (APP) through multiple cleavage steps mediated by γ-secretase, including endoproteolysis and carboxypeptidase-like trimming. The generation of neurotoxic Aβ42/43 species is enhanced by familial Alzheimer’s disease (FAD) mutations within the catalytic subunit of γ-secretase, presenilin 1 (PS1). FAD mutations of PS1 cause partial loss-of-function and decrease the cleavage activity. Activating mutations, which have the opposite effect of FAD mutations, are important for studying Aβ production. Aph1 is a regulatory subunit of γ-secretase; it is presumed to function as a scaffold of the complex. In this study, we identified Aph1 mutations that are active in the absence of nicastrin (NCT) using a yeast γ-secretase assay. We analyzed these Aph1 mutations in the presence of NCT; we found that the L30F/T164A mutation is activating. When introduced in mouse embryonic fibroblasts, the mutation enhanced cleavage. The Aph1 mutants produced more short and long Aβs than did the wild-type Aph1, without an apparent modulatory function. The mutants did not change the amount of γ-secretase complex, suggesting that L30F/T164A enhances catalytic activity. Our results provide insights into the regulatory function of Aph1 in γ-secretase activity.

    Original languageEnglish
    Article number507
    JournalInternational journal of molecular sciences
    Issue number1
    Publication statusPublished - 2022 Jan 1


    • Alzheimer’s disease
    • Amyloid beta (Aβ)
    • Aph1
    • Gamma-secretase
    • Intramembrane proteolysis
    • Saccharomyces cerevisiae

    ASJC Scopus subject areas

    • Catalysis
    • Molecular Biology
    • Spectroscopy
    • Computer Science Applications
    • Physical and Theoretical Chemistry
    • Organic Chemistry
    • Inorganic Chemistry


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