Protective effects of Zn(2+) against Abeta toxicity may be dose dependent
Tim
Evidence that the beta-amyloid plaques of Alzheimer's disease
represent the redox-silencing and entombment of abeta by zinc.
Cuajungco MP, Goldstein LE, Nunomura A, Smith MA, Lim JT, Atwood CS,
Huang X, Farrag YW, Perry G, Bush AI.
Laboratory for Oxidation Biology, Genetics and Aging Unit,
Massachusetts General Hospital, Charlestown, Massachusetts 02129, USA.
Abeta binds Zn(2+), Cu(2+), and Fe(3+) in vitro, and these metals are
markedly elevated in the neocortex and especially enriched in amyloid
plaque deposits of individuals with Alzheimer's disease (AD). Zn(2+)
precipitates Abeta in vitro, and Cu(2+) interaction with Abeta
promotes its neurotoxicity, correlating with metal reduction and the
cell-free generation of H(2)O(2) (Abeta1-42 > Abeta1-40 >
ratAbeta1-40). Because Zn(2+) is redox-inert, we studied the
possibility that it may play an inhibitory role in H(2)O(2)-mediated
Abeta toxicity. In competition to the cytotoxic potentiation caused by
coincubation with Cu(2+), Zn(2+) rescued primary cortical and human
embryonic kidney 293 cells that were exposed to Abeta1-42, correlating
with the effect of Zn(2+) in suppressing Cu(2+)-dependent H(2)O(2)
formation from Abeta1-42. Since plaques contain exceptionally high
concentrations of Zn(2+), we examined the relationship between
oxidation (8-OH guanosine) levels in AD-affected tissue and
histological amyloid burden and found a significant negative
correlation. These data suggest a protective role for Zn(2+) in AD,
where plaques form as the result of a more robust Zn(2+) antioxidant
response to the underlying oxidative attack.
PMID: 10801774 [PubMed - indexed for MEDLINE]
FULL TEXT
http://www.jbc.org/cgi/content/full/275/26/19439
Tim