Evidence that the beta-amyloid plaques of Alzheimer's disease represent the redox-silencing and entombment of abeta by zinc.
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.
Cuajungco
M P
MP
Laboratory for Oxidation Biology, Genetics and Aging Unit, Massachusetts General Hospital, Charlestown, Massachusetts 02129, USA.
Goldstein
L E
LE
Nunomura
A
A
Smith
M A
MA
Lim
J T
JT
Atwood
C S
CS
Huang
X
X
Farrag
Y W
YW
Perry
G
G
Bush
A I
AI
D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000737:chemistry* / Q000378:metabolism*; D000818:Animals; D001921:Brain / Q000378:metabolism; D002460:Cell Line; D002470:Cell Survival; D002474:Cell-Free System; D002478:Cells, Cultured; D003300:Copper / Q000378:metabolism; D006151:Guanosine / Q000378:metabolism; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism; D007150:Immunohistochemistry; D007477:Ions; D008875:Middle Aged; D009474:Neurons / Q000187:drug effects; D010084:Oxidation-Reduction; D010100:Oxygen / Q000378:metabolism; D051381:Rats; D015032:Zinc / Q000378:metabolism*
D016229:Amyloid beta-Peptides; D007477:Ions; D006151:Guanosine; D003300:Copper; D006861:Hydrogen Peroxide; D015032:Zinc; D010100:Oxygen