Contribution of redox-active iron and copper to oxidative damage in Alzheimer disease

Rudy J. Castellani, Kazuhiro Honda, Xiongwei Zhu, Adam D. Cash, Akihiko Nunomura, George Perry, Mark A. Smith*

*Corresponding author for this work

Research output: Contribution to journalReview articlepeer-review

86 Scopus citations


Metal-catalyzed hydroxyl radicals are potent mediators of cellular injury, affecting every category of macromolecule, and are central to the oxidative injury hypothesis of Alzheimer disease (AD) pathogenesis. Studies on redox-competent copper and iron indicate that redox activity in AD resides exclusively within the neuronal cytosol and that chelation with deferoxamine, DTPA, or, more recently, iodochlorhydroxyquin, removes this activity. We have also found that while proteins that accumulate in AD possess metal-binding sites, metal-associated cellular redox activity is primarily dependent on metals associated with nucleic acid, specifically cytoplasmic RNA. These findings indicate aberrations in iron homeostasis that, we suspect, arise primarily from heme, since heme oxygenase-1, an enzyme that catalyzes the conversion of heme to iron and biliverdin, is increased in AD, and mitochondria, since mitochondria turnover, mitochondrial DNA, and cytochrome C oxidative acitivity are all increased in AD. These findings, as well as studies demonstrating a reduction in microtubule density in AD neurons, suggest that mitochondrial dysfunction, acting in concert with cytoskeletal pathology, serves to increase redox-active heavy metals and initiates a cascade of abnormal events culminating in AD pathology.

Original languageEnglish (US)
Pages (from-to)319-326
Number of pages8
JournalAgeing Research Reviews
Issue number3
StatePublished - Jul 2004
Externally publishedYes


  • Alzheimer disease
  • Microtubules
  • Mitochondria
  • Oxidative stress
  • Redox metals

ASJC Scopus subject areas

  • Biotechnology
  • Biochemistry
  • Aging
  • Molecular Biology
  • Neurology


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