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Biochemical Characterization of the γ-Secretase Activity That Produces β-Amyloid Peptides

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    Biochemical Characterization of the γ-Secretase Activity That Produces β-Amyloid Peptides
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    Department of Central Nervous System and Cardiovascular Research and Department of Structural Chemistry, Schering-Plough Research Institute, Kenilworth, New Jersey 07033
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    Biochemistry

    Cite this: Biochemistry 2001, 40, 16, 5049–5055
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    https://doi.org/10.1021/bi0028800
    Published March 29, 2001
    Copyright © 2001 American Chemical Society
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    Abstract

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    Recent studies of γ-secretase have pointed out that it may be comprised of a multisubunit complex with presenilin 1 and presenilin 2 as central components. Elucidation of the biochemical mechanism of this enzymatic activity will provide important information for developing γ-secretase inhibitors in Alzheimer's disease therapy. Here we describe the biochemical characterization of γ-secretase activities using a sensitive, membrane-based assay system. Membranes were isolated from 293 cells expressing C99, the substrate of γ-secretase. Upon incubation at 37 °C, C99 is cleaved by the endogenous γ-secretase, and Aβ peptides are liberated. Aβ40 and Aβ42 γ-secretase activities are very similar in terms of their kinetic profiles and pH dependence, supporting the notion that a single enzyme is involved in both Aβ40 and Aβ42 production. Pepstatin A inhibited Aβ40 and Aβ42 γ-secretase activities with similar potency. Peptide difluoroketone and peptide aldehyde inhibitors inhibited Aβ40 production in a dose-dependent fashion, enhanced Aβ42 production at low concentrations, and inhibited Aβ42 production at high concentrations. Although the selective increase of Aβ42 by low concentrations of peptide difluoroketone and peptide aldehyde inhibitors has been reported in intact cells, the finding that this phenomenon occurs in a membrane-based assay system suggests that these compounds increase Aβ42 by a direct effect on γ-secretase. The ability of these compounds to increase Aβ42 production may reflect allosteric modulation of the γ-secretase complex by a mechanism related to that responsible for the increase of Aβ42 production by mutations in presenilins.

    Copyright © 2001 American Chemical Society

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     Address correspondence to this author at the Schering Plough Research Institute, 2015 Galloping Hill Rd., Kenilworth, NJ 07033. Tel.:  908-740-6559, Fax:  908-740-2383, Email:  [email protected].

    ‡

     Department of Central Nervous System and Cardiovascular Research.

    §

     Department of Structural Chemistry.

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    Biochemistry

    Cite this: Biochemistry 2001, 40, 16, 5049–5055
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    https://doi.org/10.1021/bi0028800
    Published March 29, 2001
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