Volume 17, Issue 9 p. 2752-2762
Full Paper

Copper(I) and Copper(II) Inhibit Aβ Peptides Proteolysis by Insulin-Degrading Enzyme Differently: Implications for Metallostasis Alteration in Alzheimer’s Disease

Dr. Giuseppe Grasso

Dr. Giuseppe Grasso

Dipartimento di Scienze Chimiche, Università di Catania, Viale Andrea Doria 6, 95125, Catania (Italy), Fax: (+39) 095-337678, Fax: (+39) 06-72596353

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Dr. Adriana Pietropaolo

Dr. Adriana Pietropaolo

Dipartimento di Scienze Chimiche, Università di Catania, Viale Andrea Doria 6, 95125, Catania (Italy), Fax: (+39) 095-337678, Fax: (+39) 06-72596353

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Prof. Giuseppe Spoto

Prof. Giuseppe Spoto

Dipartimento di Scienze Chimiche, Università di Catania, Viale Andrea Doria 6, 95125, Catania (Italy), Fax: (+39) 095-337678, Fax: (+39) 06-72596353

Istituto Biostrutture e Bioimmagini, CNR, Viale A. Doria 6, 95125, Catania (Italy)

Consorzio I.N.B.B., Viale delle Medaglie d'Oro 305, 00136, Roma (Italy)

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Dr. Giuseppe Pappalardo

Dr. Giuseppe Pappalardo

Istituto Biostrutture e Bioimmagini, CNR, Viale A. Doria 6, 95125, Catania (Italy)

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Dr. Grazia Raffaella Tundo

Dr. Grazia Raffaella Tundo

Department of Experimental Medicine and Biochemical Sciences, University of Roma Tor Vergata, Via Montpellier 1, 00133 Roma (Italy)

Interuniversity Consortium for the Research on the Chemistry of Metals in Biological Systems, Via C. Ulpiani 27, 70126 Bari (Italy)

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Dr. Chiara Ciaccio

Dr. Chiara Ciaccio

Department of Experimental Medicine and Biochemical Sciences, University of Roma Tor Vergata, Via Montpellier 1, 00133 Roma (Italy)

Interuniversity Consortium for the Research on the Chemistry of Metals in Biological Systems, Via C. Ulpiani 27, 70126 Bari (Italy)

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Prof. Massimo Coletta

Corresponding Author

Prof. Massimo Coletta

Department of Experimental Medicine and Biochemical Sciences, University of Roma Tor Vergata, Via Montpellier 1, 00133 Roma (Italy)

Interuniversity Consortium for the Research on the Chemistry of Metals in Biological Systems, Via C. Ulpiani 27, 70126 Bari (Italy)

Massimo Coletta, Department of Experimental Medicine and Biochemical Sciences, University of Roma Tor Vergata, Via Montpellier 1, 00133 Roma (Italy)

Enrico Rizzarelli, Dipartimento di Scienze Chimiche, Università di Catania, Viale Andrea Doria 6, 95125, Catania (Italy), Fax: (+39) 095-337678, Fax: (+39) 06-72596353

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Prof. Enrico Rizzarelli

Corresponding Author

Prof. Enrico Rizzarelli

Dipartimento di Scienze Chimiche, Università di Catania, Viale Andrea Doria 6, 95125, Catania (Italy), Fax: (+39) 095-337678, Fax: (+39) 06-72596353

Istituto Biostrutture e Bioimmagini, CNR, Viale A. Doria 6, 95125, Catania (Italy)

Consorzio I.N.B.B., Viale delle Medaglie d'Oro 305, 00136, Roma (Italy)

Massimo Coletta, Department of Experimental Medicine and Biochemical Sciences, University of Roma Tor Vergata, Via Montpellier 1, 00133 Roma (Italy)

Enrico Rizzarelli, Dipartimento di Scienze Chimiche, Università di Catania, Viale Andrea Doria 6, 95125, Catania (Italy), Fax: (+39) 095-337678, Fax: (+39) 06-72596353

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First published: 27 January 2011
Citations: 66

Graphical Abstract

The effect of metal ions on IDE: Metal ions, such as Cu2+, Cu+, and Ag+, have an inhibitory effect on insulin-degrading enzyme (IDE) activity (see figure). The inhibition of copper(II) is reversed by adding zinc(II), whereas the monovalent cations affect the enzyme activity irreversibly. A calyx structure is formed due to a destabilization of the hydrophobic core, occurring when Cys 812 and Cys 819 are blocked with Cu+.

Abstract

Accumulation of neurotoxic amyloid-β peptide (Aβ) and alteration of metal homeostasis (metallostasis) in the brain are two main factors that have been very often associated with neurodegenerative diseases, such as Alzheimer’s disease (AD). Aβ is constantly produced from the amyloidprecursor-protein APP precursor and immediately catabolized under normal conditions, whereas dysmetabolism of Aβ and/or metal ions seems to lead to a pathological deposition. Although insulin-degrading enzyme (IDE) is the main metalloprotease involved in Aβ degradation in the brain being up-regulated in some areas of AD brains, the role of IDE for the onset and development of AD is far from being understood. Moreover, the biomolecular mechanisms involved in the recognition and interaction between IDE and its substrates are still obscure. In spite of the important role of metals (such as copper, aluminum, and zinc), which has brought us to propose a “metal hypothesis of AD”, a targeted study of the effect of metallostasis on IDE activity has never been carried out. In this work, we have investigated the role that various metal ions (i.e., Cu2+, Cu+, Zn2+, Ag+, and Al3+) play in modulating the interaction between IDE and two Aβ peptide fragments, namely Aβ1–16 and Aβ16–28. It was therefore possible to identify the direct effect that such metal ions have on IDE structure and enzymatic activity without interferences caused by metal-induced substrate modifications. Mass spectrometry and kinetic studies revealed that, among all the metal ions tested, only Cu2+, Cu+, and Ag+ have an inhibitory effect on IDE activity. Moreover, the inhibition of copper(II) is reversed by adding zinc(II), whereas the monovalent cations affect the enzyme activity irreversibly. The molecular basis of their action on the enzyme is also discussed on the basis of computational investigations.