**4. Oxidative stress**

Oxidative stress in human body is mainly mediated by reactive oxygen species (ROS) including hydrogen peroxide (H2O2), hydroxyl free radical (•OH), superoxide (O2 •<sup>−</sup>), peroxyl (•OOR), hypochlorous acid (HOCl), nitric oxide (NO), peroxynitrite (ONOO<sup>−</sup>) and other reactive nitrogen species. Increase in concentration of these reactive species can trigger downregulation of antioxidant enzymes such as superoxide dismutase (SOD), glutathione peroxidase, catalase, thioredoxin and small molecules such as melatonin and coumarin [81]. Endogenous sources of ROS include components in mitochondrial electron transport chain and NADPH oxidase, which can trigger pathological responses leading to lipid peroxidation, DNA damage and cell death mediated by toxic products. Amyloid plaques have been shown to contain multi-fold concentrations of metals like iron (Fe), copper (Cu) and zinc (Zn) [81]. Intracellular Aβ can also trigger production of highly toxic molecules such as 4-hydroxyl-2,3-nonenal (HNE) and malandialdehyde through interactions with Fe or Cu which can catalyze Fenton reactions to generate more OH<sup>−</sup> ions. Hydroxyl radicals can also be generated from other brain ROS through Haber-Weiss reaction, particularly within mitochondria which are most prone to such oxidative damage [82]. Such ROS are generated as by-products of amyloid aggregation and are involved with metallobiology of dementia. High concentrations of Fe in brain have drastic effects in cases of dementia leading to cognitive decline through interactions with brain amyloids [83]. Metal ions are crucial for many brain functions and Fe and Cu even possess active sites for binding antioxidant SOD. However, increase in concentrations of some of these metals can cause high levels of toxicity. Twenty percent of cases in familial ALS is affected by mutation in a single enzyme SOD1 functionally affected by Cu/Zn [83]. Metal ions have propensity to bind high affinity, well-protected and redox-shielded binding sites of proteins, and in higher concentrations they can bind to other putative active sites in proteins involved in pathology of various degenerative diseases [84]. While zinc compounds have been tested for their probable therapeutic role in overcoming cognitive degeneration, Zn2+ ion has also been implicated as a contributor to formation of amyloid plaques which act as metal sinks [84]. Such mitochondrial damage and mutations have been associated with age related late-onset, non-autosomal dominant AD pathology [85].
