Formation of the 42-mer Amyloid Radical and the Therapeutic Role of Superoxide Dismutase in Alzheimer's Disease

Oxidative stress is closely involved in age-related diseases and ageing itself. There is evidence of the leading contribution of oxidative damage to neurodegenerative disease, in contrast to other diseases where oxidative stress plays a secondary role. The 42-mer amyloid β (Aβ42) peptide is thought to be a culprit in the pathogenesis of Alzheimer's disease (AD). Aβ42 aggregates form the oligomeric assembly and show neurotoxicity, causing synaptic dysfunction. Aβ42 also induces tissue oxidation (DNA/RNA, proteins, and lipids) through trace metals (Cu, Zn, and Fe), which can be protected by antioxidant enzymes, vitamin C, and vitamin E. Superoxide dismutase catalyzes the conversion of toxic superoxide radical to less reactive hydrogen peroxide, contributing to protection from AD. Here we review the involvement of oxidative stress in AD progression induced from an imbalance between the radical formation of Aβ42 itself together with unique turn structure at positions Glu22 and Asp23 and several defense systems. 1. Oxidative Stress in Ageing—The Involvement of Superoxide Radical Oxidative stress caused by reactive oxygen species (ROS) has been implicated in numerous age-related diseases and ageing itself [1, 2]. ROS include superoxide anions, hydrogen peroxide, hydroxyl radicals, and singlet oxygen. ROS are also involved in neurodegeneration such as Alzheimer’s disease (AD), Parkinson’s disease, and amyotrophic lateral sclerosis, because the brain is one of the most vulnerable tissues in the body to oxidative injuries based on its high rate of oxygen consumption [3]. The hydroxyl radical is believed to be one of the main stimuli of oxidative damage (Figure 1) and reacts with several biomolecules, leading to the formation of 8-hydroxydeoxyguanosine (8-OHdG)/8-hydroxyguanosine (8-OHG) in DNA/RNA, the formation of methionine sulfoxide, carbonylation in proteins, and lipid peroxidation. In particular, lipid peroxidation can lead to the production of 4-hydroxyl nonenal (4-HNE), malondialdehyde (MDA), and thiobarbituric acid-reacting substances (TBARS) as byproducts. The subsequent processes to hydroxyl radical could be involved in peroxynitrite formation by stimulating inducible nitric oxide synthase (i-NOS). Hydrogen peroxide (H2O2) is less reactive but is involved in the Fenton reaction (Haber-Weiss procedure, Figure 1), providing the hydroxyl radical. Figure 1: Generation of reactive oxygen species and defense systems in the cell. M red or M ox, reduced or oxidized form of metals; SOD, superoxide dismutase; GSH, reduced glutathione; GSSG, oxidized glutathione;