Redox‐Active Metals, Oxidative Stress, and Alzheimer's Disease Pathology

Abstract: Considerable evidence is mounting that dyshomeostasis of the redox‐active biometals, Cu and Fe, and oxidative stress contribute to the neuropathology of Alzheimer's disease (AD). Present data suggest that metals can interact directly with Aβ peptide, the principal component of β‐amyloid that is one of the primary lesions in AD. The binding of metals to Aβ modulates several physiochemical properties of Aβ that are thought to be central to the pathogenicity of the peptide. First, we and others have shown that metals can promote the in vitro aggregation into tinctorial Aβ amyloid. Studies have confirmed that insoluble amyloid plaques in postmortem AD brain are abnormally enriched in Cu, Fe, and Zn. Conversely, metal chelators dissolve these proteinaceous deposits from postmortem AD brain tissue and attenuate cerebral Aβ amyloid burden in APP transgenic mouse models of AD. Second, we have demonstrated that redox‐active Cu(II) and, to a lesser extent, Fe(III) are reduced in the presence of Aβ with concomitant production of reactive oxygen species (ROS), hydrogen peroxide (H2O2) and hydroxyl radical (OH•). These Aβ/metal redox reactions, which are silenced by redox‐inert Zn(II), but exacerbated by biological reducing agents, may lead directly to the widespread oxidation damages observed in AD brains. Moreover, studies have also shown that H2O2 mediates Aβ cellular toxicity and increases the production of both Aβ and amyloid precursor protein (APP). Third, the 5′ untranslated region (5′UTR) of APP mRNA has a functional iron‐response element (IRE), which is consistent with biochemical evidence that APP is a redox‐active metalloprotein. Hence, the redox interactions between Aβ, APP, and metals may be at the heart of a pathological positive feedback system wherein Aβ amyloidosis and oxidative stress promote each other. The emergence of redox‐active metals as key players in AD pathogenesis strongly argues that amyloid‐specific metal‐complexing agents and antioxidants be investigated as possible disease‐modifying agents for treating this horrible disease.