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Interplay between Copper, Neprilysin, and N-Truncation of β-Amyloid

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    Interplay between Copper, Neprilysin, and N-Truncation of β-Amyloid
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    • Mariusz Mital
      Mariusz Mital
      Florey Department of Neuroscience and Mental Health, The University of Melbourne, Melbourne, Victoria 3010, Australia
      Institute of Biochemistry and Biophysics, Polish Academy of Sciences, Warsaw, Poland
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    • Wojciech Bal
      Wojciech Bal
      Institute of Biochemistry and Biophysics, Polish Academy of Sciences, Warsaw, Poland
      More by Wojciech Bal
      Orcidhttp://orcid.org/0000-0003-3780-083X
    • Tomasz Frączyk
      Tomasz Frączyk
      Institute of Biochemistry and Biophysics, Polish Academy of Sciences, Warsaw, Poland
      Department of Immunology, Transplantology and Internal Medicine, Medical University of Warsaw, Warsaw, Poland
      More by Tomasz Frączyk
      Orcidhttp://orcid.org/0000-0003-2084-3446
    • Simon C. Drew*
      Simon C. Drew
      Department of Medicine (Royal Melbourne Hospital), The University of Melbourne, Melbourne, Victoria 3010, Australia
      *E-mail: [email protected]
      More by Simon C. Drew
      Orcidhttp://orcid.org/0000-0002-1459-9865
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    Inorganic Chemistry

    Cite this: Inorg. Chem. 2018, 57, 11, 6193–6197
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    https://doi.org/10.1021/acs.inorgchem.8b00391
    Published May 18, 2018
    Copyright © 2018 American Chemical Society
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    Abstract

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    Sporadic Alzheimer’s disease (AD) is associated with an inefficient clearance of the β-amyloid (Aβ) peptide from the central nervous system. The protein levels and activity of the Zn2+-dependent endopeptidase neprilysin (NEP) inversely correlate with brain Aβ levels during aging and in AD. The present study considered the ability of Cu2+ ions to inhibit human recombinant NEP and the role for NEP in generating N-truncated Aβ fragments with high-affinity Cu2+ binding motifs that can prevent this inhibition. Divalent copper noncompetitively inhibited NEP (Ki = 1.0 μM),  while proteolysis of Aβ yielded the soluble, Aβ4–9 fragment that can bind Cu2+ with femtomolar affinity at pH 7.4. This provides Aβ4–9 with the potential to act as a Cu2+ carrier and to mediate its own production by preventing NEP inhibition. Enzyme inhibition at high Zn2+ concentrations (Ki = 20 μM) further suggests a mechanism for modulating NEP activity, Aβ4–9 production, and Cu2+ homeostasis.

    Copyright © 2018 American Chemical Society

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    The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.inorgchem.8b00391.

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    Cited By

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    Cite this: Inorg. Chem. 2018, 57, 11, 6193–6197
    Click to copy citationCitation copied!
    https://doi.org/10.1021/acs.inorgchem.8b00391
    Published May 18, 2018
    Copyright © 2018 American Chemical Society
    Request reuse permissions

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