Abstract
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.
Highlights
Evidence that the -Amyloid Plaques of Alzheimer’s Disease Represent the Redox-silencing and Entombment of A by Zinc*
In agreement with our previous findings [5], Cu2ϩ significantly exaggerated the cytotoxicity of Amyloid- protein (A)1– 42 (18% survival), which paralleled the effects of buthionine sulfoximine (BSO)
The presence of catalase, BSO, Cu2ϩ, or Zn2ϩ alone had no significant effect on cell survival compared with untreated cells, suggesting that the effects of Cu2ϩ and Zn2ϩ in modulating A toxicity were due to interaction with the peptide
Summary
Since plaques contain exceptionally high concentrations of Zn2؉, we examined the relationship between oxidation (8-OH guanosine) levels in AD-affected tissue and histological amyloid burden and found a significant negative correlation. Modified soluble forms of A1– 42 extracted from AD brain have been shown to possess enhanced toxicity [11] These observations suggest that plaque amyloid may represent a fraction of total A in the brain that has been condensed and neutralized and no longer contributes to neurotoxicity. AD-affected histological brain sections revealed that there is an inverse correlation between plaque deposits and 8-OH guanosine (8-OHG) levels in AD-affected brain tissue These findings suggest that amyloid plaques in AD may form as a result of a more robust tissue zinc response, representing the effective quenching of abnormal A-mediated redox activity
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