Iron accumulation in Alzheimer disease is a source of redox-generated free radicals

Abstract

Damage from free radicals has been demonstrated in susceptible neuronal populations in cases of Alzheimer disease. In this study, we investigated whether iron, a potent source of the highly reactive hydroxyl radical that is generated by the Fenton reaction with H2O2, might contribute to the source of radicals in Alzheimer disease. We found, using a modified histochemical technique that relies on the formation of mixed valence iron complexes, that redox-active iron is associated with the senile plaques and neurofibrillary tangles-the pathological hallmark lesions of this disease. This lesion-associated iron is able to participate in in situ oxidation and readily catalyzes an H2O2-dependent oxidation. Furthermore, removal of iron was completely effected using deferoxamine, after which iron could be rebound to the lesions. Characterization of the iron-binding site suggests that binding is dependent on available histidine residues and on protein conformation. Taken together, these findings indicate that iron accumulation could be an important contributor toward the oxidative damage of Alzheimer disease.

Figure 1

Histochemical detection of iron in AD (A) compared with control cases (B) show striking association of iron with neurofibrillary tangles (arrowheads) and senile plaques (arrows) characteristic of the AD brain. (Scale bar = 200 μm.)

Figure 2

Lesion-associated iron (see Fig. 1A) could be completely stripped with deferoxamine (A) but readily rebound to the same sites following incubation with iron(III) citrate and iron(II) chloride (B). ∗ indicates landmark blood vessel in adjacent section. (Scale bar = 100 μm.)