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

  • 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
  • Wojciech Bal
    Wojciech Bal
    Institute of Biochemistry and Biophysics, Polish Academy of Sciences, Warsaw, Poland
    More by Wojciech Bal
  • 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
  • , and 
  • Simon C. Drew*
    Simon C. Drew
    Department of Medicine (Royal Melbourne Hospital), The University of Melbourne, Melbourne, Victoria 3010, Australia
    *E-mail: [email protected]
Cite this: Inorg. Chem. 2018, 57, 11, 6193–6197
Publication Date (Web):May 18, 2018
Copyright © 2018 American Chemical Society

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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.

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