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01-12-2008 | Original Paper

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

Authors: Silvia Bolognin, Paolo Zatta, Denise Drago, Pier Paolo Parnigotto, Fernanda Ricchelli, Giuseppe Tognon

Published in: NeuroMolecular Medicine | Issue 4/2008

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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Title: Mutual Stimulation of Beta-Amyloid Fibrillogenesis by Clioquinol and Divalent Metals
Authors: Silvia Bolognin
Paolo Zatta
Denise Drago
Pier Paolo Parnigotto
Fernanda Ricchelli
Giuseppe Tognon
Publication date: 01-12-2008
Publisher: Humana Press Inc
Published in: NeuroMolecular Medicine / Issue 4/2008
Print ISSN: 1535-1084
Electronic ISSN: 1559-1174
DOI: https://doi.org/10.1007/s12017-008-8046-x

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

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