Evidence that the β-Amyloid Plaques of Alzheimer's Disease Represent the Redox-silencing and Entombment of Aβ by Zinc

• Published in: The Journal of biological chemistry Vol. 275; no. 26; pp. 19439 - 19442
• Main Authors: Cuajungco, Math P., Goldstein, Lee E., Nunomura, Akihiko, Smith, Mark A., Lim, James T., Atwood, Craig S., Huang, Xudong, Farrag, Yasser W., Perry, George, Bush, Ashley I.
• Format: Journal Article
• Language: English
• Published: Elsevier Inc 30-06-2000
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.C000165200

Aβ binds Zn2+, Cu2+, and Fe3+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). Zn2+ precipitates Aβ in vitro, and Cu2+ interaction with Aβ promotes its neurotoxicity, correlating with metal reduction and the cell-free generation of H2O2 (Aβ1–42 > Aβ1–40 > ratAβ1–40). Because Zn2+ is redox-inert, we studied the possibility that it may play an inhibitory role in H2O2-mediated Aβ toxicity. In competition to the cytotoxic potentiation caused by coincubation with Cu2+, Zn2+ rescued primary cortical and human embryonic kidney 293 cells that were exposed to Aβ1–42, correlating with the effect of Zn2+ in suppressing Cu2+-dependent H2O2formation from Aβ1–42. 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. These data suggest a protective role for Zn2+in AD, where plaques form as the result of a more robust Zn2+ antioxidant response to the underlying oxidative attack.