3.1.1. Superoxide Dismutase

Superoxide dismutase (SOD), which belongs to the enzymatic defense system, changes the superoxide radical anion to H2O2 by oxidative decay. Another function of SOD is to protect dehydratase from free radical superoxide inactivation. There are three forms of SOD in humans. SOD-1, a copper-zinc containing SOD (Cu, Zn-SOD), is present in the cytosol and specifically catalyzes dismutation in a pH-independent medium [42]. SOD-1 protein is a homodimer composed of eight antiparallel beta strands and two metal atoms that catalyze the conversion of toxic O2 <sup>−</sup> anions to H2O2 and O2. Specifically, copper minerals play a crucial role in the catalytic function of this enzyme, while zinc is important for structural integrity [43]. SOD-1 plays an important role as a first line of defense by detoxifying superoxide radicals. In addition, the lack of this enzyme exhibited a pronounced susceptibility to paraquat toxicity. SOD-2, a manganese containing SOD (Mn-SOD), is found in the mitochondrial matrix and reduces the superoxide radical anion generated in the electron transport chain [44]. A detailed analysis revealed that the SOD-2 subunit needs one metal atom and that it is functionally disabled in the absence of Mn atoms in the active site. SOD-2 attracts O2 − and turns positive on the active side. The active metal provides electrons directly to O2 − then reduces one molecule of O2 <sup>−</sup> and one proton to be converted to form H2O2 (Figure 2). The amount of SOD-2 is different in each cell type, depending on the number of mitochondria. Specifically, the presence of SOD-2 is essential for the survival of aerobic cells and the development of cellular resistance to oxidative stress. SOD-3, an extracellular SOD (EC-SOD), also contains copper and zinc in its structure, is synthesized inside the cell and secreted into the extracellular matrix [45]. SOD-3 enzyme is not induced by its substrate or other oxidants and is regulated to coordinate with cytokines, rather than as a response of individual cells to oxidants [46].

In neurodegenerative diseases, SOD-1 and SOD-2 genes appear to be disrupted and/or mutated. SOD-1 gene mutations produce diverse cellular changes such as alteration of gene expression, unusual protein interactions, caspase activation, mitochondrial dysfunction, and cytoskeletal abnormalities in familial ALS [47]. Overexpression of SOD-1 protects neurons against the neurotoxic effects of amyloid beta (Aβ), and loss of SOD-1 accelerates aging-related pathologies and reduces lifespan in mice [48–50]. SOD-1 deficiency in an AD model showed that it was associated with augmented Aβ oligomerization and memory impairment mediated by oxidative stress [51]. Overexpression of SOD-2 by treatment with sodium orthovanadate could rescue synaptic failure and neuronal cell death in the hippocampus after kainic acid (KA)-induced oxidative stress; moreover, an increase in SOD-2 protected the neuronal death from oxidative injury [52]. Impaired SOD-2 is a common potential pathogenesis

related to oxidative stress in PD and AD [6]. In human amyloid precursor protein (hAPP) transgenic mice with over 50% reduced SOD-2 activity, increased SOD-2 protects the age-related brain against hAPP/Aβ-induced impairments [53]. Extracellularly administered SOD was effective in inhibiting cell death and restoring healthy mitochondrial morphology in a monosodium glutamate-induced excitotoxicity disease model [54]. An increase in SOD-2 can be expected to assist or improve neuronal function and vascular pathology in AD as a therapeutic effect.
