Metal ion-dependent effects of clioquinol on the fibril growth of an amyloid {beta} peptide.
Although metal ions such as Cu(2+), Zn(2+), and Fe(3+) are implicated to play a key role in Alzheimer disease, their role is rather complex, and comprehensive understanding is not yet obtained. We show that Cu(2+) and Zn(2+) but not Fe(3+) renders the amyloid beta peptide, Abeta(1-40), nonfibrillogenic in nature. However, preformed fibrils of Abeta(1-40) were stable when treated with these metal ions. Consequently, fibril growth of Abeta(1-40) could be switched on/off by switching the molecule between its apo- and holo-forms. Clioquinol, a potential drug for Alzheimer disease, induced resumption of the Cu(2+)-suppressed but not the Zn(2+)-suppressed fibril growth of Abeta(1-40). The observed synergistic effect of clioquinol and Zn(2+) suggests that Zn(2+)-clioquinol complex effectively retards fibril growth. Thus, clioquinol has dual effects; although it disaggregates the metal ion-induced aggregates of Abeta(1-40) through metal chelation, it further retards the fibril growth along with Zn(2+). These results indicate the mechanism of metal ions in suppressing Abeta amyloid formation, as well as providing information toward the use of metal ion chelators, particularly clioquinol, as potential drugs for Alzheimer disease.
Raman
Bakthisaran
B
Institute for Protein Research, Osaka University, and CREST, Japan Science and Technology Agency, Yamadaoka 3-2, Suita, Osaka 565-0871, Japan.
Ban
Tadato
T
Yamaguchi
Kei-Ichi
K
Sakai
Miyo
M
Kawai
Tomoji
T
Naiki
Hironobu
H
Goto
Yuji
Y
D000544:Alzheimer Disease / Q000188:drug therapy; D016229:Amyloid beta-Peptides / Q000187:drug effects* / Q000378:metabolism; D000891:Anti-Infective Agents, Local / Q000494:pharmacology*; D002942:Circular Dichroism; D007464:Clioquinol / Q000494:pharmacology*; D003300:Copper / Q000378:metabolism; D006801:Humans; D007501:Iron / Q000378:metabolism; D019216:Metals, Heavy / Q000378:metabolism*; D010446:Peptide Fragments / Q000187:drug effects* / Q000378:metabolism; D013056:Spectrophotometry, Ultraviolet; D013997:Time Factors; D015032:Zinc / Q000378:metabolism
D016229:Amyloid beta-Peptides; D000891:Anti-Infective Agents, Local; D019216:Metals, Heavy; D010446:Peptide Fragments; C078592:amyloid beta-protein (1-40); D003300:Copper; D007464:Clioquinol; D007501:Iron; D015032:Zinc