Dementia currently affects over 750,000 people in the UK, with Alzheimer's disease (AD) accounting for 55 % of those cases. As a result of increasing life expectancy, the number of people predicted to suffer from dementia is expected to rise to over 1.8 million by 2050. Currently there are no known cures for AD. Existing treatments at best only delay the progression of disease and accurate diagnosis can only be made with certainty at autopsy. Hence, there is an urgent need for new therapeutic approaches and for reliable and noninvasive methods to aid in the early diagnosis of AD and to give an indication of disease progression. Advanced AD is evident from the apparent progressive decline in cognitive function as a result of loss of neurons. These are accompanied by pathological changes including extracellular amyloid β plaques and intracellular changes called neurofibrillary tangles, which are abnormal deposits of hyperphosphorylated tau proteins 1.

Recent reports ascribe a major role for the metal ions, iron, copper and zinc in AD. Specifically the redox active metal ions Fe²⁺ and Cu⁺ can generate the highly reactive and oxidizing species, the hydroxyl radical via the Fenton reaction. This species is thought to account for a large proportion of oxidative modifications that are seen in AD brains including lipid peroxidation, nucleic acid oxidation and protein carbonylation. Also metal ions have been shown to be central to Aβ pathogenicity.

The Aβ peptide is a low molecular weight protein consisting of 39–43 amino acids. It has two high affinity binding sites, one specific for copper and one specific for zinc. In the Aβ1–42 peptide (the predominant Aβ species found in amyloid plaques in AD brains) the high affinity binding site binds Cu²⁺ were estimated at log K = 17.2 and 16.3 at pH 7.4 and pH 6.6 respectively, and the low affinity binding site at log K = 8.3 and 7.5 at pH 7.4 and 6.6 respectively 2. At physiological pH values, soluble Aβ is precipitated by Zn²⁺ in vitro. However, at pH levels reflecting physiological acidosis, which is characteristic of AD, in vitro precipitation of Aβ is induced by cupric and ferric ions. Cupric ions induce greater precipitation than ferric ions, which is thought to be a result of its higher binding affinity, with Aβ aggregation enhanced to ~85 % 3. In addition, Cu²⁺ ions are bound at the low affinity site completely displacing the Zn²⁺ ions in physiological acidosis 2. Levels of copper, iron and zinc have been analyzed in the rims and cores of senile plaques of AD patients and concentrations were found to be highly elevated. Concentrations exhibited in the senile plaques cores were 22.7 ± 6.5, 52.4 ± 14.5 and 67.0 ± 13.0 μg/g for copper, iron and zinc respectively 4. In addition serum copper levels have been shown to be markedly elevated in AD 5.

The catalytic effects of transition metals on the formation of reactive oxygen species are becoming evident as a major factor in AD. Aβ binds to Cu²⁺ reducing it to Cu⁺. The Aβ-Cu⁺ complex can then trap dioxygen and reduce it to hydrogen peroxide (H₂O₂). One study demonstrated that 1 μM Cu²⁺ when bound to Aβ could catalytically generate 10 μM H₂O₂, indicating continual redox cycling 6. In conditions where this reaction is not favorable, biological reducing agents such as vitamin C have been shown to enhance this reaction 7. The generation of H₂O₂ has been shown to be neurotoxic, which is considered to be a result of its reduction to the hydroxyl radical via Fenton chemistry. Cupric ion binding is dependent on histidine and tyrosine amino acid residues. Upon generation of hydroxyl radicals localized to the Cu²⁺ ion, the tyrosine residues can cross-link to form dityrosine. This further stabilizes the Aβ plaques conferring resistance to proteolysis 8. Further studies are required to establish if Aβ bound to Cu²⁺ and Zn²⁺ exhibits significant anti-oxidant enzyme activities (superoxide dismutase and catalase activities) in vivo, as many researchers have likened Aβ to the native CuZn superoxide dismutase enzyme in both its conformation and its metal binding affinities 9.

Magnetite and maghemite deposits have been found in brains of patients suffering from AD and studies are underway to correlate enhanced levels with disease progression 10. However, magnetite detection is only possible after the onset of AD. A comprehensive understanding of the levels and nature of redox-active ferric ions is warranted to assess the mechanisms of magnetite deposition. AD brains exhibit increased levels of oxidatively modified nucleic acids, specifically RNA in vulnerable neurons 11. Haem oxygenase-1 (HO-1), an enzyme which catalyses the breakdown of haem to biliverdin with release of iron and carbon monoxide, is over-expressed in the brains of AD patients. So it could be postulated that this would be one source of redox-active iron. Immunostaining of neurons demonstrated that HO-1 expression was co-localized to the neurofibrillary tangles 12. However oxidative damage to nucleic acids was reduced in neurons exhibiting neurofibrillary tangles demonstrating an antioxidant mechanism for HO-1 and an involvement in tau proteins expression. Further studies on the oxidative modifications of RNA in AD demonstrated it to be localized to iron rich lysosomes called lipofuscins originating from the mitochondria. This indicates a disruption in mitochondrial function leading to accumulation of redox-active iron in the neuronal cytoplasm 13 and subsequent reactive oxygen species generation.

Metal specific chelators afford a major opportunity for the control of metal ion mediated pathogeneses, which is not currently provided by nutraceuticals. In particular, administration of "prodrug" chelators that mimic anti-oxidant enzymes with high specificity for Cu²⁺ and Fe³⁺ ions will: i) counteract oxidative stress, ii) help to control metal ion deposition and iii) dissolve Aβ plaques and, maghemite and magnetite residues.

The author(s) declare that they have no competing interests.

The authors contributed equally to this work.