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

Abstract

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.

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; GR, glutathione reductase; GPx, glutathione peroxidase; NADPH or NADP⁺, reduced or oxidized nicotinamide adenine dinucleotide phosphate; VC, vitamin C; VE, vitamin E.

Figure 2

(a) Proposed mechanism of formation and stabilization of Aβ42 radical for long-lasting oxidative stress in AD and the toxic conformer of Aβ42 [73]. (b) Scheme of generation of Aβ42-mediated radical species (superoxide radical and hydroxyl radical) and the long-lasting Aβ42 radical in the pathogenesis of AD.