Interplay between α, β and γ-secretases determines biphasic Aβ level in the presence of a γ-secretases inhibitor

F. Ortega, J. Stott, S.A.G. Visser, C. Bendtsen

    Research output: Contribution to journalArticlepeer-review

    Abstract

    Amyloid-β (Aβ) is produced by the consecutive cleavage of Amyloid Precursor Protein (APP) first by β-secretase, generating C99, and then by γ-secretase. APP is also cleaved by α-secretase. It is hypothesized that reducing the production of Aβ in the brain may slow the progression of Alzheimer disease (AD). Therefore, different γ-secretase inhibitors (GSIs) have been developed to reduce Aβ production. Paradoxically, it has been shown that low to moderate inhibitor concentrations cause a rise in Aβ production in different cell lines, in different animal models and also in man. A mechanistic understanding of the Aβ rise remains elusive. Here, a minimal mathematical model has been developed that quantitatively describes the Aβ dynamics in cell lines which exhibit the rise as well as in cell lines which do not. The model includes steps of APP processing through both the so-called amyloidagenic and non-amyloidagenic pathway. It is shown that the cross-talk between these two pathways account for the increase in Aβ production in response to inhibitor, i.e. an increase in C99 will inhibit the non-amyloidagenic pathway redirecting APP to be cleaved by β-secretase leading to an additional increase in C99 that overcomes the loss in γ-secretase activity. With a minor extension, the model also describes plasma Aβ profiles observed in man upon dosing with a GSI. In conclusion, this mechanistic model rationalizes a series of experimental results that spans from in vitro to in vivo and to man. This has important implications for the development of drugs targeting Aβ production in AD.
    Original languageEnglish
    Article number2012 Nov 14.
    Pages (from-to)785-792
    Number of pages7
    JournalJournal of Biological Chemistry
    Volume288
    Issue number2
    DOIs
    Publication statusPublished - 11 Jan 2013

    Keywords

    • Alzheimer disease, Amyloid, Enzyme kinetics, Mathematical Modelling, Secretases, Amyloid-β Production

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