Main |
Browse Volumes |
Forthcoming Volumes |
Annals PrePrints |
Annals Extra |
E-mail Alerts |
Subscriptions & Orders |
New Proposals |
Author Guidelines |
About Annals |
Help |
 |
|
|
|
|
|
Redox-Active Metals, Oxidative Stress, and Alzheimer's Disease Pathology
XUDONG HUANGa,b,c,
ROBERT D. MOIRa,b,d,
RUDOLPH E. TANZIa,b,d,
ASHLEY I. BUSHa,b,c,e AND
JACK T. ROGERSa,b,c
aLaboratory for Oxidation Biology, bGenetics and Aging Research Unit, cDepartment of Psychiatry, dDepartment of Neurology, Massachusetts General Hospital and Harvard Medical School, Charlestown, Massachusetts 02129, USA
eMental Health Research Institute of Victoria and Department of Pathology, University of Melbourne, Parkville, Victoria 3052, Australia
Address for correspondence: Xudong Huang, Ph.D., Laboratory for Oxidation Biology, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA 02129. Voice: 617-724-9778; fax: 617-724-1823. huangx{at}helix.mgh.harvard.edu
Ann N.Y. Acad. Sci. 1012: 153-163 (2004).
Considerable evidence is mounting that dyshomeostasis of the redox-active biometals, Cu and Fe, and oxidative stress contribute to the neuropathology of Alzheimer's disease (AD). Present data suggest that metals can interact directly with Aß peptide, the principal component of ß-amyloid that is one of the primary lesions in AD. The binding of metals to Aß modulates several physiochemical properties of Aß that are thought to be central to the pathogenicity of the peptide. First, we and others have shown that metals can promote the in vitro aggregation into tinctorial Aß amyloid. Studies have confirmed that insoluble amyloid plaques in postmortem AD brain are abnormally enriched in Cu, Fe, and Zn. Conversely, metal chelators dissolve these proteinaceous deposits from postmortem AD brain tissue and attenuate cerebral Aß amyloid burden in APP transgenic mouse models of AD. Second, we have demonstrated that redox-active Cu(II) and, to a lesser extent, Fe(III) are reduced in the presence of Aß with concomitant production of reactive oxygen species (ROS), hydrogen peroxide (H 2O 2) and hydroxyl radical (OH•). These Aß/metal redox reactions, which are silenced by redox-inert Zn(II), but exacerbated by biological reducing agents, may lead directly to the widespread oxidation damages observed in AD brains. Moreover, studies have also shown that H 2O 2 mediates Aß cellular toxicity and increases the production of both Aß and amyloid precursor protein (APP). Third, the 5' untranslated region (5'UTR) of APP mRNA has a functional iron-response element (IRE), which is consistent with biochemical evidence that APP is a redox-active metalloprotein. Hence, the redox interactions between Aß, APP, and metals may be at the heart of a pathological positive feedback system wherein Aß amyloidosis and oxidative stress promote each other. The emergence of redox-active metals as key players in AD pathogenesis strongly argues that amyloid-specific metal-complexing agents and antioxidants be investigated as possible disease-modifying agents for treating this horrible disease.
Key Words: metals • oxidative stress • Alzheimer's disease • amyloid precursor protein • Aß amyloidosis • metal chelator • antioxidant
This article has been cited by other articles:
|
|
|
|
 
J. A. MCINTYRE, R. L. HAMILTON, and S. T. DEKOSKY
Redox-Reactive Autoantibodies in Cerebrospinal Fluids
Ann. N.Y. Acad. Sci.,
August 1, 2007;
1109(1):
296 - 302.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. C. Morris, D. A. Evans, C. C. Tangney, J. L. Bienias, J. A. Schneider, R. S. Wilson, and P. A. Scherr
Dietary Copper and High Saturated and trans Fat Intakes Associated With Cognitive Decline.
Arch Neurol,
August 1, 2006;
63(8):
1085 - 1088.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
Y.R. Chen, H.B. Huang, C.L. Chyan, M.S. Shiao, T.H. Lin, and Y.C. Chen
The Effect of A{beta} Conformation on the Metal Affinity and Aggregation Mechanism Studied by Circular Dichroism Spectroscopy.
J. Biochem.,
April 1, 2006;
139(4):
733 - 740.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
D. Zhu, K. S. Tan, X. Zhang, A. Y. Sun, G. Y. Sun, and J. C.-M. Lee
Hydrogen peroxide alters membrane and cytoskeleton properties and increases intercellular connections in astrocytes
J. Cell Sci.,
August 15, 2005;
118(16):
3695 - 3703.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
B. Angeletti, K. J. Waldron, K. B. Freeman, H. Bawagan, I. Hussain, C. C. J. Miller, K.-F. Lau, M. E. Tennant, C. Dennison, N. J. Robinson, et al.
BACE1 Cytoplasmic Domain Interacts with the Copper Chaperone for Superoxide Dismutase-1 and Binds Copper
J. Biol. Chem.,
May 6, 2005;
280(18):
17930 - 17937.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
W. W. Smith, D. D. Norton, M. Gorospe, H. Jiang, S. Nemoto, N. J. Holbrook, T. Finkel, and J. W. Kusiak
Phosphorylation of p66Shc and forkhead proteins mediates A{beta} toxicity
J. Cell Biol.,
April 25, 2005;
169(2):
331 - 339.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
T. J. Nelson and D. L. Alkon
Oxidation of Cholesterol by Amyloid Precursor Protein and {beta}-Amyloid Peptide
J. Biol. Chem.,
February 25, 2005;
280(8):
7377 - 7387.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
