OS occurs when the production of free radicals or their products are in excess of antioxi-dant defense mechanisms. OS, resulting from increased formation of hydrogen peroxide and oxygen-derived free radicals, can damage biological molecules and initiate a cascade of events, including dysfunction of mitochondrial respiration, excitotoxicity, and a fatal rise in cytosolic calcium, and, thus, is a major factor of the cytopathology of many neurodegenerative disorders (84). The generation of ROS during early-stage protein aggregation may be a common, fundamental molecular mechanism underlying the pathogenesis of oxidative damage, neurodegeneration and cell death in different neuro-degenerative diseases. However, it remains unclear how mitochondrial oxidative stress may induce neuronal death. In a variety of tissues, cumulative oxidative stress, disrupted mitochondrial respiration, and mitochondrial damage are associated with, and may indeed promote cell death and degeneration (84a,b). Perturbations in the physiological function of mitochondria inevitably disturb cell function, sensitize cells to neurotoxic insults and may initiate cell death, all significant phenomena in the pathogenesis of a number of neurode-generative disorders including AD (84c,d). Drugs that specifically target this process could be useful in the future therapy of these diseases (44,85). There is a possible involvement of a mutant APP and its derivatives in causing mitochondrial oxidative damage, suggesting that the formation of A and other derivatives of APP are key factors in cellular changes in the AD brain, including the generation of free radicals, and leading to oxidative damage in neurons from AD, its cell, and tg mouse models (86). Among the various free radicals generated in the living organism, hydroxyl radical and peroxynitrite are the most potent and can damage cells via non-selective oxidation of proteins, lipids, fatty acids, and nucleic acid (87-89). They are formed via the Haber-Weiss and Fenton reaction between H2O2 and reduced transition metals (usually iron II or copper) (see (90) for review). Proteins are initial targets of ROS, and protein radicals generated by ROS can oxidize GSH, suggesting that radicals are important for oxidative stress (91). In AD, aberrant metal homeostasis may contribute to the formation of ROS and toxic AP oligomers, thus, facilitating the formation of amyloid plaques (92). Alternatively, not superoxide itself but the protoneated form, the hydroxyl radical, can initiate lipid peroxidation reactions. Another mechanism of lipid peroxidation has been attributed to increased formation of peroxynitrite from nitric oxide (NO) and superoxide. Reduction of the resulting oxidized transition metal ions (Fe(II) or Cu(II)) by vitamin C or other reductants regenerates the "active" transition metal and leads to the process of redox cycling and the catalytic production of free radicals. Cellular reductants are often diminished in neurodegenerative disorders (93), further supporting their involvement in redox cycling and a decrease in autooxidant defense. Increases in oxidative damage do not necessitate that the cell is succumbing to OS, given that cells may have increased their defenses sufficiently to compensate for the increased flux of reactive oxygen responsible for the damage. This concept is critically outlined by evidence suggesting that cells which fail to compensate for oxidative imbalance (stress) enter apop-tosis with rapid cell death, while those with compensatory response to ROS (antioxidant enzymes, low molecular weight reductants, etc.) may show long-term survival. Numerous sources of free radicals are present in the brain, e.g. from oxidative phosphorylation of adenosine 5'diphosphate (ADP) to adenosine triphosphate (ATP), glutamate-mediated excitotoxicity, diminished energy metabolism forming ROS, enzymatic oxidative deam-ination of catecholamines by monoaminoxidase (MAO), activated microglia, aggregated P amyloid, and several trace metals, that provide a microenvironment in which excess generation of free radicals can lead to OS. These ROS can react with cellular macromole-cules through oxidation and cause the cells undergo necrosis or apoptosis. The control of the redox environment of the cell provides addition regulation in the signal transduction pathways which are redox sensitive. Recently, many researches focus on the relationship between apoptosis and oxidative stress. However, till now, there is no clear and defined mechanism showing how oxidative stress could contribute to the apoptosis, and the fact that OS plays a key role in the regulation and control of the cell survival and cell death through its interaction with cellular macromolecules and signal transduction pathway ultimately may help in developing an unique therapy for the treatment of these neurodegenerative disorders (93a). Alterations in metal homeostasis induce increased production of free radicals, primarily catalyzed by iron or copper, being directly involved in the neurodegenerative process in various disorders (90,94-96). These indications suggest a direct cause-effect relationship between disruption in metal homeostasis and the increased oxida-tive damage; brain ferritin iron being a risk factor for age at onset of neurodegenerative diseases (97).
The metalloenzymes mangan and CuZn superoxide dismutate (SOD-1 and SOD-2) are considered the primary defense against substantial buildup of reactive oxygen because they remove O2, the initial form of metabolically derived reactive oxygen, while the enzymes catalase and peroxidase remove H2O2. Several transgenic and knock-out animal models suggest that decrease in MnSOD activity in vivo can explain the increase in mitochondrial oxidative damage and, consequently, mitochondrial impairment (98).
Although the precise sources of increased oxidative damage are not fully clear, the findings of increased localization of redox-active transition metals in brain regions most affected by neurodegeneration is consistent with their contribution to OS. Free radical oxygen chemistry plays an important pathogenic role in all these conditions, though it is as yet undetermined what types of oxidative damage occur early in the pathogenic cascade and which ones are secondary manifestation of dying neurons (87). Recent results suggest that hydrogen peroxide accumulates during the incubation of P amyloid or a-synuclein and hyperphosphorylated tau that show a close interrelationship (99), synergistic action (58,100), and induce a mutual fibrillation (27,101), by a metal-dependent mechanism. This is subsequently converted to hydroxyl radicals by the addition of Fe(II) by Fenton's reaction, one of the fundamental mechanisms underlying neurodegenerative processes as a direct sequelae of H2O2 production during the formation of abnormal protein aggregates (102).
Iron is a powerful promoter of free radical damage, able to catalyze generation of highly reactive hydroxyl, alkoxyl, and peroxyl radicals from H2O2 and lipid peroxides, respectively. Although most iron in the brain is stored in ferritin, "catalytic" iron is readily mobilized from injured brain tissue. As a result of a loss of iron homeostasis, the brain becomes vulnerable to iron-induced OS (103). There is increasing evidence that iron misregulation is involved in the mechanisms that underlie many neurodegenerative disorders (104-106). Conditions such as neuroferritinopathy (107,108) and Friedreich ataxia (FRDA) are associated with mutations in genes that encode proteins involved in iron metabolism, and as the brain ages, iron accumulates in regions that are affected by AD and PD (109).
Increased levels of oxidative damage to DNA, lipids, and proteins have been detected in postmortem tissues from patients with PD, AD, ALS, PSP, and related disorders, and at least some of these changes may occur early in disease progression (85,103,110). Recent studies showed that lipid peroxidation is an early event in the brain in amnestic MCI suggesting that oxidative damage occurs early in the pathogenesis of AD (111). Toxic interactions between reactive transition metals and free radicals are regulated by reduced glutathione (GSH). Perturbations of its metabolism are documented in neurodegenerative disorders, associated with abnormalities in copper homeostasis (112) and redox balance (104,113). Oxidative damage has been shown to be the earliest event in AD (106,114,114a,115,116), PD, other neurodegenerative processes, but also in normal aging (101,117). Recent studies suggest that oxidative damage to nuclear and mitochondrial DNA occurs in the earliest detectable phase of AD and may play a meaningful role in the pathogenesis of this disease (118,119). High concentrations of reactive iron can increase OS-induced neuronal vulnerability, and iron accumulation might increase the toxicity of environmental or endgenous substances. Examination of distinct antibodies against neurofibrillary tangles (NFTs) that recognize unique epitopes of tau in AD after treatment with 4-hydroxy-2-nonenal (HNE) recognized tau only in the phosphorylated state. These findings not only support the idea that OS is involved in NFT formation, but also show that HNE modifications of tau promote and contribute to the generation of the major conformational properties defining NFTs (120). The accumulation and precipitation of proteins may be aggravated by OS, and may, in turn, cause more oxida-tive damage by interfering with the function of the proteasome. Proteasomal inhibition increases levels of OS not only to proteins but also to other biomolecules (121). Recent studies explored the role of redox metals and oxidative abnormalities in human prion diseases (122).
In both human AD and transgenic mouse models of AD, oxidative damage occurs preceding A deposition that further contribute to OS and neurodegeneration (123). Mutant APP and its derivates are involved in the generation of free radicals in mitochondria and cause mitochondrial oxidative damage, linking A$, generation of free radicals, and oxidative damage in the pathogenesis of AD (86). Increasing evidence suggests that oxidative stress/damage (A£, iron/hydrogen peroxide) or neurotoxic by-products of lipid peroxidation (4-hydroxy-2-nonenal, acrolein) lead to cell death through apoptosis or programmed cell death in AD (123a). Major components are lipid and protein peroxidation, glycosi-dation with DNA oxidation and formation of advanced glycation endproducts (AGEs), protein-bound oxidation products of sugar (120,124-126). In AD, PD, and other neu-rodegenerative disorders, the production of AGEs has been observed. Since they are both markers of transitional metal-induced OS and inducers of protein cross-linking and free radical formation, they may reflect early disease-specific changes rather than late epiphenomena (127). AGEs co-localize with inducible NO synthase in AD, particularly in amyloid plaques, astrocytes, and microglia supporting the evidence of an AGE-induced OS in the vicinity of these marker lesions. Co-incident with the reduced energy metabolism during the development of the disease, some of the key mitochondrial enzymes have shown deficient activity in AD neurons, which may lead to increased ROS production. However, oxidative damage occurs primarily within the cytoplasm rather than in mitochondria. ROS levels appear to be correlated with age rather than with a specific dementing disorder, suggesting that oxidative imbalance observed in AD could be due to a decreased total antioxidant capacity (128). Given that SOD activity is increased in AD mitochondria and that metal ions are enriched in susceptible neurons, it was hypothesized that mitochondria, as a source, provide hydrogen peroxide, which, as an intermediate, once in the cytoplasm, will be converted into highly reactive hydroxyl radicals through Fenton reaction in the presence of metal ion and cause damage in the cytoplasm (129). Oxidative damage in AD shows its reduction in those neurons with the most severe cytopathology (130), and damage to DNA and RNA repair is particularly severe in the hippocampus, the earliest and most severely involved brain area. This suggests oxidative defenses extend beyond the classical antioxidant enzymes and low-molecular weight reductants. RNA is extensively modified in AD and, while clearly damaged, its rapid turnover may also serve a protective function. While RNA alteration may lead to protein sequence anomalies, its destruction can more easily be accommodated in cellular metabolism than damage to DANN or enzyme-active site destruction. The large pool of neuronal RNA may even mean that errors in protein synthesis, resulting from oxidatively modified RNA, can be corrected by the metabolic turnover of abnormal proteins. Two enzymes, mitochondrial glutamate dehydrogenase and cytosolic malate dehydrogenase, are increased in frontal cortex of AD brain, but showed a decreased degree of oxidation when compared to controls (131).
These data suggest that oxidative imbalance is met by a series of complex reactions to establish a disease-related homeostasis balance (126,132,133). In PD, many biochemical changes indicate compromised antioxidant systems suggested to underlie cellular vulnerability to progressive OS which generates excessive ROS or free radicals selectively in SN with subsequent cell damage (95,134-136).
• Significant increase of iron in the SNp with a shift of Fe(II): Fe(III) of 2:1 as compared to 1:2 in controls. Sequestration of redox-active iron and aberrant accumulation of ferric iron causing the formation of OH radicals via the Fenton reaction suggests that the iron-catalyzed oxidative reaction plays a significant role in a-synuclein aggregation in vivo. Neuromelanin, a product of dopamine auto-oxidation, is capable of forming a complex with iron, thereby potentiating the generation of free radicals and the aggregation of a-synuclein. Loss of soluble a-synuclein, by its aggregation, can increase dopamine synthesis with accompanying increased generation of reactive metabolites, finally leading to degeneration (136-138).
• Sequestration of redox-active iron in LBs of PD SN substantiates the OS hypothesis, while the absence of redox-active iron in neocortical LBs highlights a fundamental difference between cortical and brain stem LBs (104,134).
• Both reduced GSH, an important compound of antioxidative defense and protein repair, and GSH peroxidase activity (destroys H2O2) are decreased in SN of PD patients and in incidental LB disease (preclinical PD), probably preceding both complex I and dopamine loss (139).
• SOD, an enzyme indicative of superoxide generation, shows increase of both isoenzymes (Cu-Zn-SOD and Mn-SOD) in PD SN suggesting increased superoxide generation. The recent finding of oxidative modification and aggregation of Cu-Zn-SOD in spontaneous AD and PD suggests that these disorders may share a common or overlapping pathogenic mechanism(s) with ALS (140).
• Postmortem studies reported increased basal levels of thiobarbituric acid-reactive substances in SN of PD, a secondary product of lipid peroxidation, coupled with a decrease in polyunsaturated fatty acids, the substrates for lipid peroxidation.
• Increase of intracellular 8-hydroxydeoxyguanosine (8-HOG), produced by free radical damage in DNA in SN neurons corresponds to its degeneration pattern (141). Increased peripheral 8-HOG levels in MSA, AD, and ALS suggest that systemic DNA/RNA oxidation is commonly observed in these diseases (142).
• NO that, as free radical, may induce increased lipid peroxidation, release of Fe2+, damage to DNA, and inhibition of cytochrome c oxidase (COX) and SOD, and damage mitochondrial function by inhibiting complexes II-IV, is often increased in several neurodegenerative diseases (143).
• Peroxynitrite, formed by reduced SOD, induces aggregation of a-synuclein in situ, and nitrated a-synuclein is found in the core of LBs (135,144) indicating its involvement in damaging structural proteins.
• Cross-linking of a-synuclein by AGEs has been observed in PD and in incidental LB disease, suggesting that AGE-promoted LB formation may reflect early disease-specific changes rather than late epiphenomena (145). Widespread accumulation of nitrated a-synuclein in LBs provides evidence to directly link oxidative and nitrative damages.
Demonstration of hydroxynonenal (HNE) products in LBs indicates that peroxidation may play a critical role in their formation (146). a-Synuclein has been shown to produce neuronal death due to OS and promotion of mitochondrial defects (147,148).
• Co-localization of a-synuclein and 3-nitrotyrosine (3-NT), a marker of protein nitration, through oxidative mechanisms has been observed in LBs and dystrophic neurites in DLB and GCIs in MSA, whereas most "pale bodies" and Lewy neurites in hippocampus lack 3-NT immunoreactivity, suggesting that nitration is not a prerequisite for a-synuclein deposition (149).
• Genetic studies have implicated OS in PD pathogenesis indicating OS response (150-154).
• In the MPTP model of parkinsonism, ADP depletion and ROS overproduction occur soon after MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) application, subjecting the intoxicated cells to an early energy crisis and OS. Among the essential molecular pathways that are pivotal in triggering cell-death cascades, alterations in ATP synthesis and ROS production lead to the demise of the affected neurons (155).
• Chronic systemic treatment of rats with rotenone, a pesticide known to inhibit mitochondria, causes selective nigrostriatal dopaminergic degeneration with associated inclusions containing fibrillar a-synuclein (156). Rotenone treatment may induce an increase in oxidative stress in the dopaminergic neurons, which in turn may facilitate fibrilliza-tion of a-synuclein, providing a link between oxidative stress and pathogenesis of synucleionopathies (157,158).
Many of the above factors may participate in the pathogenesis of several experimental models of PD indicating a multi-component process involving both OS and mitochondrial dysfunction, complex I inhibition, etc. (135,159). The cytotoxic action of iron-induced OS in PD and AD is compared in Table 2.
OS is also recognized as a major pathogenic factor in other neurodegenerative disorders, e.g. in HD, where in both human brain and in transgenic mouse models, increased indices of a number of OS markers have been reported (160). Production of lipid peroxidation, e.g. HNE and malondialdehyde are increased in both AD and PSP and their occurrence is proportional to the extent of tau pathology (161,162). Cdk5 is a kinase regulating outgrowth of neurites and modulating the noxious effect of hyperperoxidation on tau protein through the overproduction of the kinase involved in tau hyperphosphoryla-tion. Abnormal processing of p53, the regulatory subunit of cdk5, in AD is a major source of phosphorylated tau aggregates. In PSP, total cdk5 protein levels, in contrast to AD, are more than threefold increased and co-localized with tau immunoreactivity, indicating that in PSP this alteration is different from that in AD which may be due to the absence of Ap protein deposition (163).
Increased OS has also been described in ALS, where disruption of Zn metabolism in motoneurons is important in both sporadic and familial ALS (164). Enhanced basal oxidoradical products, lipid peroxide, perturbed calcium homeostasis, and increased nitrotyrosine in lower motoneurons of both transgenic mice and human ALS are present (165). Zn-deficient SOD induces apoptosis in motoneurons through a mechanism involving peroxynitrite, which could explain why mitochondrial damage is the earliest marker of injury in ALS-SOD mutant mice (164). In the ALS animal models, as in the human diseases, certain residual motor neurons showed overexpression of peroxiredoxin-II (PrxII)
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