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Peptidomimetic Probes and Molecular Modeling Suggest That Alzheimer's γ-Secretase Is an Intramembrane-Cleaving Aspartyl Protease

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    Peptidomimetic Probes and Molecular Modeling Suggest That Alzheimer's γ-Secretase Is an Intramembrane-Cleaving Aspartyl Protease†
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    Department of Pharmaceutical Sciences, University of Tennessee, Memphis, Tennessee 38163, and Center for Neurologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Boston, Massachusetts 02115
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    Biochemistry

    Cite this: Biochemistry 1999, 38, 15, 4720–4727
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    https://doi.org/10.1021/bi982562p
    Published March 26, 1999
    Copyright © 1999 American Chemical Society
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    Abstract

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    The amyloid β-protein (Aβ), implicated in the pathogenesis of Alzheimer's disease (AD), is a proteolytic metabolite generated by the sequential action of β- and γ-secretases on the amyloid precursor protein (APP). The two main forms of Aβ are 40- and 42-amino acid C-terminal variants, Aβ40 and Aβ42. We recently described a difluoro ketone peptidomimetic (1) that blocks Aβ production at the γ-secretase level [Wolfe, M. S., et al. (1998) J. Med. Chem.41, 6−9]. Although designed to inhibit Aβ42 production, 1 also effectively blocked Aβ40 formation. Various amino acid changes in 1 still resulted in inhibition of Aβ40 and Aβ42 production, suggesting relatively loose sequence specificity by γ-secretase. The alcohol counterparts of selected difluoro ketones also lowered Aβ levels, indicating that the ketone carbonyl is not essential for activity and suggesting that these compounds inhibit an aspartyl protease. Selected compounds inhibited the aspartyl protease cathepsin D but not the cysteine protease calpain, corroborating previous suggestions that γ-secretase is an aspartyl protease with some properties similar to those of cathepsin D. Also, since the γ-secretase cleavage sites on APP are within the transmembrane region, we consider the hypothesis that this region binds to γ-secretase as an α-helix and discuss the implications of this model for the mechanism of certain forms of hereditary AD.

    Copyright © 1999 American Chemical Society

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    †

     This work supported by NIH Grants NS 37537 (M.S.W.), HL 3536 (I.O.D.), and AG 12749 (D.J.S.) and a Faculty Development Grant from the University of Tennessee College of Pharmacy (M.S.W.).

    *

     To whom correspondence should be addressed. Telephone:  (901) 448-7533. Fax:  (901) 448-6828. E-mail:  [email protected].

    ‡

     University of Tennessee.

    §

     Harvard Medical School and Brigham and Women's Hospital.

    Cited By

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    This article is cited by 250 publications.

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    Biochemistry

    Cite this: Biochemistry 1999, 38, 15, 4720–4727
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    https://doi.org/10.1021/bi982562p
    Published March 26, 1999
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