Mutual stimulation of beta-amyloid fibrillogenesis by clioquinol and divalent metals.
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 beta-amyloid (A beta) 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 A beta either alone or complexed with Cu(2+) and Zn(2+). Surprisingly, our data indicated that CQ promoted rather than inhibited the formation of A beta 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 A beta, 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 A beta 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 + A beta-metals. Based on the present findings, the literature data on the potential effectiveness of CQ-based chelation therapy in AD should be re-interpreted.
Bolognin
Silvia
S
Department of Biology, Padova Metalloproteins Unit, CNR-Institute of Biomedical Technologies, University of Padova, Via Ugo Bassi 58B, 35121, Padova, Italy.
Zatta
Paolo
P
Drago
Denise
D
Tognon
Giuseppe
G
Parnigotto
Pier Paolo
PP
Ricchelli
Fernanda
F
D000544:Alzheimer Disease / Q000378:metabolism* / Q000503:physiopathology / Q000628:therapy; D019943:Amino Acid Substitution / Q000187:drug effects / Q000502:physiology; D016229:Amyloid beta-Peptides / Q000187:drug effects* / Q000378:metabolism / Q000648:ultrastructure; D000818:Animals; D045744:Cell Line, Tumor; D015913:Chelation Therapy / Q000009:adverse effects / Q000379:methods; D007464:Clioquinol / Q000494:pharmacology*; D003300:Copper / Q000633:toxicity; D004357:Drug Synergism; D006801:Humans; D008670:Metals / Q000737:chemistry / Q000633:toxicity*; D009498:Neurotoxins / Q000633:toxicity; D058225:Plaque, Amyloid / Q000187:drug effects* / Q000378:metabolism / Q000648:ultrastructure; D051381:Rats; D013045:Species Specificity; D015032:Zinc / Q000633:toxicity
D016229:Amyloid beta-Peptides; D008670:Metals; D009498:Neurotoxins; D003300:Copper; D007464:Clioquinol; D015032:Zinc