Abeta is a metal binding protein which accumulates together with elevations of zinc, copper and iron in the brain in AD. Abeta interactions with these metals mediate the precipitation of the peptide, but binding of the redox active metal ions (Cu and Fe) engenders their reduction and the O2-dependent, cell-free generation of H2O2. H2O2 is formed most by Abeta1-42> Abeta1-40>rat Abeta, a rank order that mirrors involvement of the peptides in amyloid pathology, and also the respective H2O2-mediated toxicity of each peptide. These findings are important because there is a striking enrichment of Cu, Fe, and Zn in amyloid deposits in AD, accompanied by signs of severe oxidation stress in the neocortex, and because Abeta amyloid deposition in transgenic animals induces similar oxidation markers. We have also found that Abeta in the brain in AD bears carbonyl adducts which form as consequence of H2O2-mediated attack and may induce protease resistance. We have also found that although Zn precipitates Abeta, it also inhibits Cu reduction, H2O2 formation, and Abeta neurotoxicity, suggesting that its enrichment in plaque may represent a homeostatic defense. We hypothesize that plaque may become oxidatively inert as a consequence of concentrating Zn, and indeed may form because of the interaction of zinc with oxidized Abeta. This possibility is supported by recent data indicating an inverse correlation between plaque load and oxidation markers in AD brain. The overall goal of this competing renewal is to clarify the complex relationship between cerebral Cu, Zn, and Fe levels, amyloid formation and oxidative damage, in human post-mortem and amyloid-bearing transgenic animal brain tissue. We hypothesize that elevated Cu and Fe potentiate the oxidation damage caused by Abeta, but that Zn quenches Abeta-mediated oxidation at the expense of forming amyloid. Using inductively coupled plasma spectrometry, we will measure the enrichment of Cu, Zn, and Fe in the brains of APP transgenic animals as a consequence of developmental amyloid deposition. We will test whether targeting the metal interaction with Abeta with a bioavailable chelating compound that crosses the BBB inhibits Abeta toxicity and amyloid formation in vivo, as the basis for a potential therapeutic strategy. Finally, we will cross the ZnT3 knockout mouse that lacks vesicular zince in its neocortex with the APP2576 amyloid-bearing transgenic to determine whether this pool of brain zinc contributes to amyloid formation and if this knockout will attenuate amyloid formation.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG012686-09
Application #
6616176
Study Section
Special Emphasis Panel (ZRG1-MDCN-2 (01))
Program Officer
Snyder, Stephen D
Project Start
1994-05-01
Project End
2005-08-31
Budget Start
2003-09-01
Budget End
2004-08-31
Support Year
9
Fiscal Year
2003
Total Cost
$259,500
Indirect Cost
Name
Massachusetts General Hospital
Department
Type
DUNS #
073130411
City
Boston
State
MA
Country
United States
Zip Code
02199
Duce, James A; Bush, Ashley I (2010) Biological metals and Alzheimer's disease: implications for therapeutics and diagnostics. Prog Neurobiol 92:1-18
Duce, James A; Tsatsanis, Andrew; Cater, Michael A et al. (2010) Iron-export ferroxidase activity of ?-amyloid precursor protein is inhibited by zinc in Alzheimer's disease. Cell 142:857-67
Strozyk, Dorothea; Launer, Lenore J; Adlard, Paul A et al. (2009) Zinc and copper modulate Alzheimer Abeta levels in human cerebrospinal fluid. Neurobiol Aging 30:1069-77
Bush, Ashley I; Tanzi, Rudolph E (2008) Therapeutics for Alzheimer's disease based on the metal hypothesis. Neurotherapeutics 5:421-32
Nagano, Seiichi; Bush, Ashley I (2008) Sensitive, selective, and irreversible inhibition of cyclooxygenase-2 activity by copper. ChemMedChem 3:223-5
White, Anthony R; Du, Tai; Laughton, Katrina M et al. (2006) Degradation of the Alzheimer disease amyloid beta-peptide by metal-dependent up-regulation of metalloprotease activity. J Biol Chem 281:17670-80
Adlard, Paul A; Bush, Ashley I (2006) Metals and Alzheimer's disease. J Alzheimers Dis 10:145-63
Maynard, Christa J; Cappai, Roberto; Volitakis, Irene et al. (2006) Gender and genetic background effects on brain metal levels in APP transgenic and normal mice: implications for Alzheimer beta-amyloid pathology. J Inorg Biochem 100:952-62
Religa, D; Strozyk, D; Cherny, R A et al. (2006) Elevated cortical zinc in Alzheimer disease. Neurology 67:69-75
Melov, Simon; Wolf, Norman; Strozyk, Dorothea et al. (2005) Mice transgenic for Alzheimer disease beta-amyloid develop lens cataracts that are rescued by antioxidant treatment. Free Radic Biol Med 38:258-61

Showing the most recent 10 out of 17 publications