Oxidative Stress and Redox-Active Iron in Alzheimer's Disease

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Abstract

Many lines of evidence indicate that oxidative stress is one of the earliest events in the genesis of Alzheimer's disease (AD). Iron is a transition metal capable of generating hydroxyl radicals, the most potent reactive oxygen species. Consequently, a disruption in the metabolism of iron has been postulated to have a role in the pathogenesis of AD. Indeed, both senile plaques and neurofibrillary tangles, the major pathological landmarks of AD, as well as neurons in the earliest stages of the disease, show elevated iron deposition. However, it is clear that the iron bound to lesion-associated proteins such as amyloid-beta and tau plays only a minor, late role in the disease, with the RNA-associated iron found in the neuronal cytoplasm occurring early and being of paramount importance. In this regard, it is probably not surprising that there is significant oxidation of cytoplasmic RNA among the populations of neurons vulnerable to AD. In this review, we consider the role of iron-induced oxidative stress as a key event in AD pathophysiology.

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Apolipoprotein E allele-specific antioxidant activity and effects on cytotoxicity by oxidative insults and beta-amyloid peptides.

M. Miyata, J. D. Smith (1996)

The apolipoprotein E (APOE) E4 allele is associated with Alzheimer's disease, cardiovascular disease, and decreased longevity. To probe the mechanism of these associations, cell lines were created which secrete each apoE isoform. ApoE conditioned media, purified apoE, and commercially obtained apoE protected B12 cells from hydrogen peroxide cytotoxicity with E2 > E3 > E4. Physiological levels of apoE protected cells from beta-amyloid peptides, while higher doses of apoE led to increased cytotoxicity. E2 > E3 > E4 possessed antioxidant activity, and apoE bound certain metal ions. The decreased antioxidant activity of E4 could contribute to its association with Alzheimer's disease, cardiovascular disease and decreased longevity.

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A histochemical study of iron, transferrin, and ferritin in Alzheimer's diseased brains.

B Mufson, Stephen Connor, Corinne S. Martin … (1991)

Immunohistochemical and histochemical staining were performed on Alzheimer's diseased brain tissue obtained at autopsy. The iron-regulatory proteins transferrin and ferritin as well as iron are, in general, found predominantly in oligodendrocytes similar to that previously reported for normal brain tissue. However, in the vicinity of senile plaques, the staining pattern is altered for both proteins and iron. Transferrin is homogenously distributed around the senile plaques and is apparently extracellular. In addition, transferrin is found in astrocytes in the cerebral cortical white matter of the Alzheimer's tissue rather than its normal distribution in oligodendrocytes. A robust ferritin immunoreaction accompanies senile plaques and many blood vessels in the Alzheimer's brain tissue. Although many ferritin-positive oligodendrocytes are present in the Alzheimer's tissue, most of the ferritin-containing cells associated with senile plaques and blood vessels are microglia. Iron can also be demonstrated in the senile plaques. The iron reaction product is observed both diffusely in proximity of the plaques and in cells associated with the plaques. These data strongly suggest a disruption in brain iron homeostasis in Alzheimer's disease as demonstrated by alterations in the normal cellular distribution of iron and the proteins responsible for iron regulation. These data will contribute to understanding both the potential for oxidative damage and the potential for metal neurotoxicity in Alzheimer's disease.