Adventiously-bound redox active iron and copper are at the center of oxidative damage in Alzheimer disease.

Abstract

Central to oxidative damage in Alzheimer disease is the production of metal-catalyzed hydroxyl radicals that damage every category of macromolecule. Studies on redox-competent copper and iron indicate that redox activity in Alzheimer disease resides exclusively within the cytosol of vulnerable neurons and that chelation with deferoxamine or DTPA removes this activity. We have also found that while proteins that accumulate in Alzheimer disease such as tau, amyloid beta, and apolipoprotein E possess metal-binding sites, metal-associated cellular redox activity is more dependent on metal-nucleic acid binding. Consistent with this finding is the large amount of cytoplasmic RNA in pyramidal neurons. Still, the source of metal-catalyzed redox activity is controversial. Heme oxygenase-1, an enzyme that catalyzes the conversion of heme to iron and biliverdin, is increased in Alzheimer disease suggesting increased heme turnover as a source of redox-active iron. Additionally, the role of mitochondria as a potential source of redox-active metals and oxygen radical production is assuming more prominence. In recent studies, we have found that while mitochondrial DNA and cytochrome C oxidase activity are increased in Alzheimer disease, the number of mitochondria is decreased, indicating accelerated mitochondria turnover. This finding, as well as preliminary studies demonstrating a reduction in microtubule density in neurons in Alzheimer disease suggests mitochondrial dysfunction as a potentially inseparable component of the initiation and progression of Alzheimer disease.

• Authors: George Perry, Marta A Taddeo, Robert B Petersen, Rudy J Castellani, Peggy L R Harris, Sandra L Siedlak, Adam D Cash, Quan Liu, Akohiko Nunomura, Craig S Atwood, Mark A Smith
• Journal: Biometals : an international journal on the role of metal ions in biology, biochemistry, and medicine (Biometals) Vol. 16 Issue 1 Pg. 77-81 (Mar 2003) ISSN: 0966-0844 [Print] Netherlands
• PMID: 12572666 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S., Review)

Chemical References

• Hydroxyl Radical
• Copper
• Iron
• Electron Transport Complex IV

Topics

• Alzheimer Disease (metabolism, pathology)
• Brain (metabolism, pathology)
• Copper (metabolism)
• Electron Transport Complex IV (metabolism)
• Humans
• Hydroxyl Radical (metabolism)
• Iron (metabolism)
• Models, Neurological
• Oxidation-Reduction
• Oxidative Stress