Metals, oxidative stress and neurodegenerative disorders. K. Jomova, D. Vondrakova, M.
Lawson, and M. Valko, Mol. Cell. Biochem., 345, 91–104 (2010).
The neurodegenerative diseases, Alzheimer's disease (AD) and Parkinson's disease (PD), areage-related disorders characterized by the deposition of abnormal forms of specific proteins in thebrain. AD is characterized by the presence of extracellular amyloid plaques and intraneuronal
neurofibrillary tangles in the brain. Biochemical analysis of amyloid plaques revealed that the main
constituent is fibrillar aggregates of a 39-42 residue peptide referred to as the amyloid-β protein (Aβ).
PD is associated with the degeneration of dopaminergic neurons in the substantia nigra pars
compacta. One of the pathological hallmarks of PD is the presence of intracellular inclusions called
Lewy bodies that consist of aggregates of the presynaptic soluble protein called α-synuclein. Thereare various factors influencing the pathological depositions, and in general, the cause of neuronal
death in neurological disorders appears to be multifactorial.
However, it is clear, that the underlying factor in the neurological disorders is increasedoxidative stress substantiated by the findings that the protein side-chains are modified either directly
by reactive oxygen species (ROS) or reactive nitrogen species (RNS), or indirectly, by the productsof lipid peroxidation. The increased level of oxidative stress in AD brain is reflected by the increased
brain content of iron (Fe) and copper (Cu) both capable of stimulating free radical formation (e.g.
hydroxyl radicals via Fenton reaction), increased protein and DNA oxidation in the AD brain,enhanced lipid peroxidation, decreased level of cytochrome c oxidase and advanced glycation end
products (AGEs), carbonyls, malondialdehyde (MDA), peroxynitrite, and heme oxygenase-1 (HO-1).
AGEs, mainly through their interaction with receptors for advanced glycation end products (RAGEs),
further activate signaling pathways, inducing formation of proinflammatory cytokines such as
interleukin-6 (IL-6). The conjugated aromatic ring of tyrosine residues is a target for free-radical
attack, and accumulation of dityrosine and 3-nitrotyrosine has also been reported in AD brain. The
oxidative stress linked with PD is supported by both postmortem studies and by studies showing theincreased level of oxidative stress in the substantia nigra pars compacta, demonstrating thus thecapacity of oxidative stress to induce nigral cell degeneration. Markers of lipid peroxidation include
4-hydroxy-trans-2-nonenal(HNE),

4-oxo-trans-2-nonenal(4-ONE),

acrolein,and4-oxo-trans-2-hexenal, all of which are well recognized neurotoxic agents. In addition, otherimportant factors, involving inflammation, toxic action of nitric oxide (NO·), defects in protein
clearance, and mitochondrial dysfunction all contribute to the etiology of PD.
It has been suggested that several individual antioxidants or their combinations can beneuroprotective and decrease the risk of AD or slow its progression. The aim of this review is todiscuss the role of redox metals Fe and Cu and non-redox metal zinc (Zn) in oxidative stress-related
etiology of AD and PD. Attention is focused on the metal-induced formation of free radicals and theprotective role of antioxidants [glutathione (GSH), vitamin C (ascorbic acid)], vitamin E(α-Tocopherol), lipoic acid, flavonoids [catechins, epigallocatechin gallate (EGCG)], and curcumin.
An alternate hypothesis topic in AD is also discussed.