Interplay between Copper, Neprilysin, and N-Truncation of β-Amyloid
- Mariusz MitalMariusz MitalFlorey Department of Neuroscience and Mental Health, The University of Melbourne, Melbourne, Victoria 3010, AustraliaInstitute of Biochemistry and Biophysics, Polish Academy of Sciences, Warsaw, PolandMore by Mariusz Mital
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- Wojciech BalWojciech BalInstitute of Biochemistry and Biophysics, Polish Academy of Sciences, Warsaw, PolandMore by Wojciech Bal
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- Tomasz FrączykTomasz FrączykInstitute of Biochemistry and Biophysics, Polish Academy of Sciences, Warsaw, PolandDepartment of Immunology, Transplantology and Internal Medicine, Medical University of Warsaw, Warsaw, PolandMore by Tomasz Frączyk
- , and
- Simon C. Drew*Simon C. Drew*E-mail: [email protected]Department of Medicine (Royal Melbourne Hospital), The University of Melbourne, Melbourne, Victoria 3010, AustraliaMore by Simon C. Drew
Abstract
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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