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Mutual Stimulation of Beta-Amyloid Fibrillogenesis by Clioquinol and Divalent Metals

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An Erratum to this article was published on 30 August 2008

Abstract

As reported by some authors, clioquinol (CQ), a 8-hydroxyquinoline derivative, has produced very encouraging results in the treatment of Alzheimer’s disease (AD). Its biological effects are most likely ascribed to complexation of specific metal ions, such as copper (II) and zinc (II), critically associated with β-amyloid (Aβ) aggregation/fibrillogenesis and degeneration processes in the brain. The present study was aimed at assessing the in vitro effects of CQ on the aggregation/fibrillogenesis properties of human Aβ either alone or complexed with Cu2+ and Zn2+. Surprisingly, our data indicated that CQ promoted rather than inhibited the formation of Aβ fibrillar aggregates when added metal ions were present. To understand whether the latter effects were related to the peptide amino acid sequence, we also investigated the aggregational profile of rat Aβ, which differs from the human homologous for three amino acidic substitutions. Such a sequence alteration drastically reduced the tendency of the peptide to undergo spontaneous aggregation/fibrillization. In the presence of CQ and metals, however, also rat Aβ showed a strong propensity to generate fibrillar aggregates. In agreement with the pro-aggregation effects observed in solution, studies with neuroblastoma cells demonstrated an impairment of cell functioning only in the presence of CQ + Aβ–metals. Based on the present findings, the literature data on the potential effectiveness of CQ-based chelation therapy in AD should be re-interpreted.

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Acknowledgements

This work was supported by a grant from CNR/MIUR (FIRB no. RBNE03PX83). We gratefully acknowledge Prof. Luigi Messori and Dr. Chiara Gabbiani for helpful discussions.

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Authors and Affiliations

  1. Department of Biology, Padova “Metalloproteins” Unit, CNR-Institute of Biomedical Technologies, University of Padova, Via Ugo Bassi 58B, 35121, Padova, Italy

    Silvia Bolognin, Paolo Zatta, Denise Drago, Fernanda Ricchelli & Giuseppe Tognon

  2. Department of Pharmaceutical Sciences, University of Padova, Padova, Italy

    Pier Paolo Parnigotto

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  1. Silvia Bolognin
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  2. Paolo Zatta
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  3. Denise Drago
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  5. Fernanda Ricchelli
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  6. Giuseppe Tognon
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Correspondence to Fernanda Ricchelli.

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An erratum to this article can be found at http://dx.doi.org/10.1007/s12017-008-8050-1

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Bolognin, S., Zatta, P., Drago, D. et al. Mutual Stimulation of Beta-Amyloid Fibrillogenesis by Clioquinol and Divalent Metals. Neuromol Med 10, 322–332 (2008). https://doi.org/10.1007/s12017-008-8046-x

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