Mutual stimulation of beta-amyloid fibrillogenesis by clioquinol and divalent metals

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

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Pages (from-to)322-332
Number of pages11
JournalNeuroMolecular Medicine
Volume10
Issue number4
DOIs
Publication statusPublished - Dec 2008

Keywords

  • β-Amyloid
  • Aggregation/fibrillogenesis
  • Clioquinol
  • Metal ions

ASJC Scopus subject areas

  • Cellular and Molecular Neuroscience
  • Molecular Medicine
  • Neurology

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