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 H 2 O 2 , 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 H 2 O 2 -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.

A non-toxic ligand for voxel-based MRI analysis of plaques in AD transgenic mice

“…This direct detection of amyloid lesions most likely reflects iron content within plaques (Falangola et al, 2005;Jack et al, 2004Jack et al, , 2005Vanhoutte et al, 2005;. Iron deposition has been previously reported both in AD and in transgenic AD mouse model plaques, in particular in more mature lesions (Smith et al, 1997(Smith et al, , 1998. We detected plaques without contrast agent mainly in older animals and in large plaques, most likely related to the increased iron content within some of these more mature lesions.…”

Biometals and Their Therapeutic Implications in Alzheimer's Disease

“…Iron elevation in AD brains, first demonstrated in 1953 [99], is a consistently reported finding [99][100][101][102][103][104][105][106][107][108]. Neuronal iron deposition causes oxidative stress via the Fenton reaction, which might contribute to elevated oxidative stress observed in the AD brain [109].…”

Mechanisms by which metals promote events connected to neurodegenerative diseases

“…These results suggest that alterations in IRP-2 may be directly linked to impaired iron homeostasis in AD. We have found a marked association of redox-active iron with both NFT and SP in AD [100].…”