Increasing evidence demonstrates that oxidative stress causes damage to cell function with aging and is involved in a number of age-related disorders including atherosclerosis, arthritis, and neurodegenerative disorders. In the neurodegenerative diseases, oxidative stress has been implicated in amyotrophic lateral sclerosis, Parkinson disease, Huntington disease, and Alzheimer disease AD.

The neurodegenerative disorder receiving the most attention has been AD, in which an increase occurs in oxidation of brain lipids, carbohydrates, proteins, and DNA. Some of the products of oxidation have been found in the major histopathologic alterations in AD: the neurofibrillary tangles NFTs and senile plaques reviewed in Markesbery and Carney 1 and Ceballos-Picot 2.

These oxidative modifications are closely associated with a subtle inflammatory process in the brain in AD. Oxidative stress refers to a state in which free radicals and their products are in excess of antioxidant defense mechanisms. This imbalance can occur as a result of increased free radical production or a decrease in antioxidant defenses.

Free radicals are defined as any atom or molecule that has one or more unpaired electrons in its outer shell.

The reduction of molecular oxygen to water is a major source of potent radicals. The initial step in this reaction yields the superoxide radical, which produces hydrogen peroxide by addition of an electron. The reduction of hydrogen peroxide yields the highly reactive hydroxyl radical. These radicals plus singlet oxygen are called reactive oxygen species ROS.

Several reactive nitrogen species, nitric oxide, and peroxynitrite also are important modulators of oxidative stress. These free radicals and others are capable of reacting with lipids, proteins, nucleic acids, and other molecules and altering their structure and function.

Oxidative stress can lead to alterations in cells with an accumulation of oxidized products such as aldehydes and isoprostanes from lipid peroxidation, protein carbonyls from protein oxidation, and base adducts from DNA oxidation, all of which serve as markers of oxidation.

Because the brain is largely composed of easily oxidized lipids, has a high oxygen consumption rate, and lacks strong antioxidant defenses, it is quite vulnerable to oxidative injury.

It has been demonstrated that there is an increase in oxidation in the brain with aging, which is the most consistent risk factor for AD. Another factor that makes the brain more susceptible to oxidation in AD is the presence of increased iron, a critical element in the generation of ROS.

The gradual accumulation of oxidative damage over time in postmitotic neurons could account for the late-life onset and gradually progressive nature of the decline in AD.

The remainder of the oxygen is reduced to hydrogen peroxide and the superoxide radical. Under stressful conditions and in aging, the electron transport system can increase ROS formation considerably.

Thus, the mitochondria are both a source and a target of toxic ROS. Mitochondrial dysfunction and oxidative metabolism may play an important role in the pathogenesis of AD and other neurodegenerative diseases see Beal 3 for review.

Reduced cytochrome oxidase activity and messenger RNA levels have been found in autopsied brains of patients with AD. Using cybrid techniques, researchers have shown that AD cytochrome oxidase defects can be transferred into cybrid cell lines that demonstrate increased cytosolic calcium concentrations and an increase in free radical production.

Increased lipid peroxidation occurs in the brain in AD and is most prominent where degenerative changes are most pronounced. Decreases in polyunsaturated fatty acids, primarily arachidonic and docosahexaenoic acids, accompany lipid peroxidation in AD.

Oxidation of polyunsaturated fatty acids produces aldehydes, one of the most important of which is 4-hydroxynonenal HNE , a highly reactive cytotoxic substance capable of inhibiting glycolysis, nucleic acid and protein synthesis, and degrading proteins.

Four-hydroxynonenal levels are increased in autopsied specimens from multiple brain regions and in the cerebrospinal fluid CSF in subjects with AD, and HNE adducts are present in NFTs. Four-hydroxynonenal causes degeneration and death of cultured hippocampal neurons by impairing ion-motive adenosine triphosphatase activity and disrupting calcium homeostasis.

Four-hydroxynonenal impairs glucose and glutamate transport and is capable of inducing apoptosis in cultured neurons. Administration of HNE into the basal forebrain of rats causes damage to cholinergic neurons, diminished choline acetyltransferase, and impaired visuospatial memory. The F 2 -isoprostanes are prostaglandin-like compounds that are formed nonenzymatically by free radical—induced oxidation of arachidonic acid.

Oxidation of docosahexaenoic acid forms F 4 -neuroprostanes. F 2 -isoprostanes are elevated in postmortem ventricular CSF of subjects with AD, 8 and in the lumbar CSF from living patients with probable AD, but not in the CSF from living patients with amyotrophic lateral sclerosis.

This suggests that these quantifiable markers of brain lipid peroxidation potentially could be used to assess the efficacy of therapeutic agents to decrease lipid peroxidation in AD. The oxidation of proteins by free radicals may also play a meaningful role in AD. Hydrazide-reactive protein carbonyl is a general assay of oxidative damage to protein.

Several studies demonstrate an increase in protein carbonyls in multiple brain regions in subjects with AD and in their NFTs.

Two enzymes that are especially sensitive to oxidative modification are glutamine synthetase and creatine kinase, both of which are markedly diminished in the brains of subjects with AD.

Oxidative alterations in glutamine synthetase could cause alteration of glutamate concentrations and enhance excitotoxicity, whereas oxidative impairment of creatine kinase could cause diminished energy metabolism in AD. Pathologic aggregation of proteins into fibrils is a characteristic of AD.

Oxidative modifications can cause crosslinking of covalent bonds of proteins leading to fibril formation and insolubility. Neurofibrillary tangles are characterized by the aggregation and hyperphosphorylation of tau proteins into paired helical filaments.

Phosphorylation is linked to oxidation through the microtubule-associated protein kinase pathway and through the activation of the transcription factor NFκB, thus potentially linking oxidation to the hyperphosphorylation of tau proteins. Oxidation of cysteine in tau protein controls the in vitro assembly of paired helical filaments.

The role of oxidation damage in NFT formation is supported by the presence of protein carbonyls, nitrotyrosine a marker of the potent radical peroxynitrite , HNE, acrolein another highly reactive aldehyde product of lipid peroxidation , advanced glycation end products AGE , and hemeoxygenase-1 an antioxidant enzyme in NFTs.

Oxidation of DNA can produce strand breaks, sister chromatid exchange, DNA-protein crosslinking, and base modifications. The DNA damage accumulating in nondividing mammalian cells may play a major role in aging-associated changes.

Several studies demonstrate an increase in oxidative DNA damage in the brains of subjects with AD see Gabbita et al 11 for review. Elevations of 5-hydroxyuracil, 8-hydroxyadenine, and 5-hydroxycytosine levels also have been found in nuclear brain fractions in subjects with AD.

The pattern of damage to multiple bases is most likely due to hydroxyl radical attack on DNA. In addition, oxidative stress may not be the only cause of the disease. It should be noted that other deleterious processes such as inflammation and excitotoxicity also could be involved in the pathogenesis of neurodegenerative disease [ ].

Therefore, it would be necessary to apply the combination of antioxidants with other drugs or multifunctional agents in treating neurodegenerative diseases.

Third, it is plausible that one single antioxidant may not be sufficient to resist the oxidative damage since the oxidative stress is modulated by a complex system of endogenous and exogenous antioxidants.

In this regard, the combinatory approach of antioxidants would be necessary to be studied in the treatment of neurodegenerative diseases [ , ]. Fourth, the timing of antioxidant therapy might not be optimal in previous clinical trials.

Most trials have assessed the efficacy of antioxidants in patients with advanced AD or PD. Given that antioxidants may exert a prophylactic role in neurodegenerative disease, the earlier application of antioxidants, even before the onset of symptoms, may be effective [ , ].

The optimization of time and duration of antioxidant therapy would be necessary to be elucidated. Fifth, inter-individual differences in the levels of endogenous antioxidants may affect responses to antioxidant therapy [ ]. Before starting antioxidant treatment, it might be helpful to select participants who could be the potential responders such as those with low levels of endogenous antioxidants, rather than the probable non-responders with high or normal levels of endogenous antioxidants [ ].

The role of oxidative stress in the pathogenesis of neurodegenerative diseases has been well demonstrated in many preclinical and clinical studies. However, the benefit of antioxidant therapy for neurodegenerative diseases is still controversial in human, although the pre-clinical studies have shown promising results.

One of reasons for such discrepancy would be that there was no effective measurement of oxidative stress in the brain. Unfortunately, peripheral biomarkers may not necessarily represent oxidative stress in the brain and changes in neuronal function.

Therefore, proper central biomarkers for oxidative stress should be identified to detect objective benefits to the brain and find exact therapeutic targets in treating neurodegenerative diseases. DPRCT: double-blind, placebo-controlled, randomized clinical trial, MAOI: monoamine oxidase inhibitor, ADCS-ADL: alzheimer's disease cooperative study-activities of daily living, MMSE: mini-mental status examination, ADAS-total: alzheimer's disease assessment scale-total score, ADAS-Cog: alzheimer's disease assessment scale-cognitive subcomponent, CGIC: clinical global impression of change, UPDRS: unified parkinson disease rating scale.

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The Role of Oxidative Stress in Neurodegenerative Diseases Geon Ha Kim 1,2 , Jieun E. Received : August 20, ; Revised : September 14, ; Accepted : September 14, Types of reactive oxygen species ROS Oxygen is susceptible to radical formation due to two unpaired electrons present in the outer electron shell [ 6 ].

Mitochondrial ROS production The mitochondrion is the primary source of ROS production in the majority of cells. NADPH oxidases Nox Nox, a transmembrane enzyme complex, is known to be another important endogenous source of O 2 - production as the result of the catalyzing the electron transfer from NADPH to oxygen [ 19 , 20 ].

Xanthine oxidases XO XO and xanthine dehydrogenase XDH are inter-convertible forms of xanthine oxidoreductase [ 32 ]. ROS production in the endoplasmic reticulum The endoplasmic reticulum ER is the membrane-based intracellular organelle that is primarily related to protein folding and lipid biosynthesis [ 10 , 36 ].

ROS production in peroxisomes Peroxisomes are present in most eukaryotic cells and participate in multiple metabolic pathways including fatty acid oxidation, phospholipid biosynthesis, amino acid catabolism, and oxidative part of the pentose phosphate pathway [ 10 , 39 ].

Superoxide dismutase SOD SOD plays a significant role in catalyzing the breakdown of highly reactive O 2 - to less reactive H 2 O 2 and oxygen [ 33 ]. Glutathione peroxidases GPX GPX contains a family of multiple isoenzymes which catalyze the reduction of H 2 O 2 and lipid peroxides utilizing GSH as an electron donor [ 2 , 33 ].

Catalase Catalase is responsible for the conversion of H 2 O 2 to water and oxygen using either iron or manganese as a cofactor [ 2 , 33 , 43 ]. Peroxiredoxins PRX PRX are thiol-specific peroxidases that catalyze the reduction of H 2 O 2 as well as other organic hydroperoxides and peroxynitrite [ 33 , 44 , 45 ].

Glutathione GSH GSH, a tripeptide synthesized from glutamate, cysteine, and glycine, exerts protective function of cell survival against oxidative stress [ 2 , 33 ]. Vitamin E Vitamin E is a lipid-soluble antioxidant that can attenuate the effects of peroxide and protect against lipid peroxidation in cell membranes [ 2 , 33 ].

Vitamin C Vitamin C is a water-soluble antioxidant, which is involved in the removal of free radicals by electron transfer and also acts as a cofactor for antioxidant enzymes [ 3 , 33 ]. Physiological functions of ROS Low to moderate levels of ROS are critical in cellular signaling and pro-survival pathways [ 3 , 5 , 40 , 58 ].

Oxidative stress: excessive accumulation of ROS In a healthy condition, the production of ROS is balanced by various antioxidant systems [ 2 , 33 ]. Alzheimer's disease Alzheimer's disease AD , as one of the most common neurodegenerative diseases, is characterized by progressive neuronal loss and accumulation of proteins including extracellular amyloid plaques Aβ and intracellular tau tangles neurofibrillary tangles, NFT [ 70 ].

Parkinson's disease Parkinson's disease PD is a neurodegenerative disorder characterized by selective neuronal loss of dopaminergic DA neurons in the substantia nigra pars compacta SNc and decreased DA levels in the nigrostriatal DA pathway in the brain [ 85 , 86 ].

Measurement of oxidative stress in peripheral blood Since oxidative stress may be a common pathophysiological mechanism underlying various neurodegenerative diseases, several surrogate markers for oxidative stress or antioxidant activity, including circulating lipid peroxides, GSH, and vitamins C and E, have been assessed in peripheral blood [ 69 , 95 , 96 , 97 , 98 ].

Magnetic Resonance Spectroscopy Glutathione GSH GSH is currently the only antioxidant which can be measured using 1 H magnetic resonance spectroscopy MRS [ ]. Vitamin C Ascorbic acid The concentration of vitamin C is approximately 1. Positron Emission Tomography [ 62 Cu] diacetyl-bis N 4 -methylthiosemicarbazone [ 62 Cu] ATSM [ 62 Cu] diacetyl-bis N 4 -methylthiosemicarbazone [ 62 Cu] ATSM is a radiotracer for positron emission tomography PET that can measure intracellular over-reductive state [ ].

Electron paramagnetic resonance EPR spectroscopy EPR spectroscopy has been considered as one of possible methods to detect and characterize the radicals in vivo [ ]. Clinical studies with antioxidant therapy in neurodegenerative diseases Antioxidants are divided into endogenous or exogenous agents.

Possible reasons for little efficacy of antioxidants in treating neurodegenerative diseases The following explanations may address why the current clinical trials have not yet found the potential antioxidants, which would effectively treat neurodegenerative diseasess.

Common reactive oxygen species ROS. The consecutive reduction of oxygen through adding electrons cause the formation of a variety of ROS, which include superoxide O 2 - , hydroxyl radical ·OH , hydroxyl ion OH - and hydrogen peroxide H 2 O 2. The red dot indicates an unpaired electron.

Generation of ROS. The superoxide O 2 - is generated from O 2 as a by-product of respiratory chain complex in the mitochondria or by NADPH oxidase. By superoxide dismutase SOD , the superoxide O 2 - can be transformed into hydrogen peroxide H 2 O 2 , which can be further transformed to a number of other ROS such as hydroxyl radicals ·OH and hydroxyl anions OH -.

Table 1 A summary of antioxidants in clinical studies for neurodegenerative diseases DPRCT: double-blind, placebo-controlled, randomized clinical trial, MAOI: monoamine oxidase inhibitor, ADCS-ADL: alzheimer's disease cooperative study-activities of daily living, MMSE: mini-mental status examination, ADAS-total: alzheimer's disease assessment scale-total score, ADAS-Cog: alzheimer's disease assessment scale-cognitive subcomponent, CGIC: clinical global impression of change, UPDRS: unified parkinson disease rating scale.

Lin MT, Beal MF. Mitochondrial dysfunction and oxidative stress in neurodegenerative diseases. Nature ; Gandhi S, Abramov AY. Mechanism of oxidative stress in neurodegeneration. Oxid Med Cell Longev ; Song P, Zou MH. In: Wang H, Patterson C.

Atherosclerosis: risks, mechanisms, and therapies. Federico A, Cardaioli E, Da Pozzo P, Formichi P, Gallus GN, Radi E.

Mitochondria, oxidative stress and neurodegeneration. J Neurol Sci ; Patten DA, Germain M, Kelly MA, Slack RS. Reactive oxygen species: stuck in the middle of neurodegeneration.

J Alzheimers Dis ;SS Held P. An introduction to reactive oxygen species: measurement of ROS in cells white paper. BioTek Instruments, Inc. Bolisetty S, Jaimes EA. Mitochondria and reactive oxygen species: physiology and pathophysiology. Int J Mol Sci ; Halliwell B. Oxidative stress and neurodegeneration: where are we now?.

J Neurochem ; Zorov DB, Juhaszova M, Sollott SJ. Mitochondrial reactive oxygen species ROS and ROS-induced ROS release. Physiol Rev ; Mani S. In: Rani V, Yadav UC. Free radicals in human health and disease. New Delhi: Springer, ; Orrenius S. Reactive oxygen species in mitochondria-mediated cell death.

Drug Metab Rev ; Widlansky ME, Gutterman DD. Regulation of endothelial function by mitochondrial reactive oxygen species. Antioxid Redox Signal ; Cadenas E, Davies KJ. Mitochondrial free radical generation, oxidative stress, and aging.

Free Radic Biol Med ; Mancuso M, Coppede F, Migliore L, Siciliano G, Murri L. Mitochondrial dysfunction, oxidative stress and neurodegeneration.

J Alzheimers Dis ; Quinlan CL, Perevoshchikova IV, Hey-Mogensen M, Orr AL, Brand MD. Sites of reactive oxygen species generation by mitochondria oxidizing different substrates. Redox Biol ; McLennan HR, Degli Esposti M. The contribution of mitochondrial respiratory complexes to the production of reactive oxygen species.

J Bioenerg Biomembr ; Yankovskaya V, Horsefield R, Törnroth S, Luna-Chavez C, Miyoshi H, Léger C, Byrne B, Cecchini G, Iwata S. Architecture of succinate dehydrogenase and reactive oxygen species generation. Science ; Turrens JF. Mitochondrial formation of reactive oxygen species. J Physiol ; Infanger DW, Sharma RV, Davisson RL.

NADPH oxidases of the brain: distribution, regulation, and function. Babior BM. NADPH oxidase. Curr Opin Immunol ; Lambeth JD. NOX enzymes and the biology of reactive oxygen. Nat Rev Immunol ; Regulation of NAD P H oxidases by AMPK in cardiovascular systems.

Görlach A, Brandes RP, Nguyen K, Amidi M, Dehghani F, Busse R. A gp91phox containing NADPH oxidase selectively expressed in endothelial cells is a major source of oxygen radical generation in the arterial wall. Circ Res ; Bengtsson SH, Gulluyan LM, Dusting GJ, Drummond GR.

Novel isoforms of NADPH oxidase in vascular physiology and pathophysiology. Clin Exp Pharmacol Physiol ; Wingler K, Wünsch S, Kreutz R, Rothermund L, Paul M, Schmidt HH. Upregulation of the vascular NAD P H-oxidase isoforms Nox1 and Nox4 by the renin-angiotensin system in vitro and in vivo.

Van Buul JD, Fernandez-Borja M, Anthony EC, Hordijk PL. Expression and localization of NOX2 and NOX4 in primary human endothelial cells. Clempus RE, Sorescu D, Dikalova AE, Pounkova L, Jo P, Sorescu GP, Schmidt HH, Lassègue B, Griendling KK.

Nox4 is required for maintenance of the differentiated vascular smooth muscle cell phenotype. Arterioscler Thromb Vasc Biol ; Ellmark SH, Dusting GJ, Fui MN, Guzzo-Pernell N, Drummond GR.

The contribution of Nox4 to NADPH oxidase activity in mouse vascular smooth muscle. Cardiovasc Res ; Bedard K, Krause KH. The NOX family of ROS-generating NADPH oxidases: physiology and pathophysiology. Gordillo G, Fang H, Park H, Roy S. Noxdependent nuclear H2O2 drives DNA oxidation resulting in 8-OHdG as urinary biomarker and hemangioendothelioma formation.

Dikalov SI, Dikalova AE, Bikineyeva AT, Schmidt HH, Harrison DG, Griendling KK. Distinct roles of Nox1 and Nox4 in basal and angiotensin II-stimulated superoxide and hydrogen peroxide production. Abramov AY, Scorziello A, Duchen MR. Three distinct mechanisms generate oxygen free radicals in neurons and contribute to cell death during anoxia and reoxygenation.

J Neurosci ; Dasuri K, Zhang L, Keller JN. Oxidative stress, neurodegeneration, and the balance of protein degradation and protein synthesis.

Harrison R. Structure and function of xanthine oxidoreductase: where are we now?. Physiological roles of xanthine oxidoreductase.

Bhandary B, Marahatta A, Kim HR, Chae HJ. An involvement of oxidative stress in endoplasmic reticulum stress and its associated diseases. Higa A, Chevet E. Redox signaling loops in the unfolded protein response. Cell Signal ; Malhotra JD, Kaufman RJ. Endoplasmic reticulum stress and oxidative stress: a vicious cycle or a double-edged sword?.

Schrader M, Fahimi HD. Peroxisomes and oxidative stress. Biochim Biophys Acta ; Valko M, Leibfritz D, Moncol J, Cronin MT, Mazur M, Telser J. Free radicals and antioxidants in normal physiological functions and human disease. Int J Biochem Cell Biol ; Power JH, Blumbergs PC. Cellular glutathione peroxidase in human brain: cellular distribution, and its potential role in the degradation of Lewy bodies in Parkinson's disease and dementia with Lewy bodies.

Acta Neuropathol ; Brigelius-Flohé R, Maiorino M. Glutathione peroxidases. Dröge W. Free radicals in the physiological control of cell function. Espinosa-Diez C, Miguel V, Mennerich D, Kietzmann T, Sánchez-Pérez P, Cadenas S, Lamas S. Antioxidant responses and cellular adjustments to oxidative stress.

Wood ZA, Schröder E, Robin Harris J, Poole LB. Structure, mechanism and regulation of peroxiredoxins. Trends Biochem Sci ; Oberley TD, Verwiebe E, Zhong W, Kang SW, Rhee SG.

Localization of the thioredoxin system in normal rat kidney. Seo MS, Kang SW, Kim K, Baines IC, Lee TH, Rhee SG. Identification of a new type of mammalian peroxiredoxin that forms an intramolecular disulfide as a reaction intermediate.

J Biol Chem ; Hall A, Nelson K, Poole LB, Karplus PA. Structure-based insights into the catalytic power and conformational dexterity of peroxiredoxins. Winterbourn CC, Metodiewa D. The reaction of superoxide with reduced glutathione. Arch Biochem Biophys ; Winterbourn CC. Reconciling the chemistry and biology of reactive oxygen species.

Nat Chem Biol ; Marinho HS, Real C, Cyrne L, Soares H, Antunes F. Hydrogen peroxide sensing, signaling and regulation of transcription factors. Lee M, Cho T, Jantaratnotai N, Wang YT, McGeer E, McGeer PL. Depletion of GSH in glial cells induces neuro-toxicity: relevance to aging and degenerative neurological diseases.

FASEB J ; Dringen R, Gutterer JM, Hirrlinger J. Glutathione metabolism in brain metabolic interaction between astrocytes and neurons in the defense against reactive oxygen species. Eur J Biochem ; Dringen R.

Metabolism and functions of glutathione in brain. Prog Neurobiol ; Dringen R, Hirrlinger J. Glutathione pathways in the brain. Biol Chem ; Presnell CE, Bhatti G, Numan LS, Lerche M, Alkhateeb SK, Ghalib M, Shammaa M, Kavdia M. Computational insights into the role of glutathione in oxidative stress.

Curr Neurovasc Res ; Song J, Kang SM, Lee WT, Park KA, Lee KM, Lee JE. Glutathione protects brain endothelial cells from hydrogen peroxide-induced oxidative stress by increasing nrf2 expression. Exp Neurobiol ; Groeger G, Quiney C, Cotter TG. Hydrogen peroxide as a cell-survival signaling molecule.

Braidy, N. PLoS One 6:e Brewer, G. Epigenetic oxidative redox shift EORS theory of aging unifies the free radical and insulin signaling theories.

Burcham, P. Internal hazards: baseline DNA damage by endogenous products of normal metabolism. Bürkle, A. Poly ADP-ribosyl ation and aging. PubMed Abstract Google Scholar.

Burney, S. The chemistry of DNA damage from nitric oxide and peroxynitrite. Google Scholar. Canossa, M. Nitric oxide down-regulates brain-derived neurotrophic factor secretion in cultured hippocampal neurons. Carney, J. Reversal of age-related increase in brain protein oxidation, decrease in enzyme activity, and loss in temporal and spatial memory by chronic administration of the spin-trapping compound N-tert-butyl-alpha-phenylnitrone.

Castellano, J. Age-related memory impairment is associated with disrupted multivariate epigenetic coordination in the hippocampus. PLoS One 7:e Castelli, V. Neuronal cells rearrangement during aging and neurodegenerative disease: metabolism, oxidative stress and organelles dynamic.

Chabita, K. Reactions of OH and eaq- adducts of cytosine and its nucleosides or nucleotides with Cu II ions in dilute aqueous solutions: a steady-state and pulse radiolysis study. Chance, B. Hydroperoxide metabolism in mammalian organs. Childs, B. Cellular senescence in aging and age-related disease: from mechanisms to therapy.

Chouliaras, L. Aging 34, — Chwang, W. The nuclear kinase mitogen-and stress-activated protein kinase 1 regulates hippocampal chromatin remodeling in memory formation. Cosi, C. Brain Res. Critchley, M. And all the daughters of musick shall be brought low: language function in the elderly.

Cutler, R. Introduction: the adversities of aging. Ageing Res. Age-dependent deterioration of nuclear pore complexes causes a loss of nuclear integrity in postmitotic cells. Cell , — De Boer, J. Premature aging in mice deficient in DNA repair and transcription. De Bont, R. Endogenous DNA damage in humans: a review of quantitative data.

Mutagenesis 19, — Deak, M. EMBO J. DeFedericis, H. Singlet oxygen-induced DNA damage. Degerman, S. Maintained memory in aging is associated with young epigenetic age. Aging 55, — Ditaranto, K. Donato, A.

SIRT-1 and vascular endothelial dysfunction with ageing in mice and humans. Douki, T. Peroxynitrite mediated oxidation of purine bases of nucleosides and isolated DNA. Free Radic. Dubey, H. Duke, C.

Experience-dependent epigenomic reorganization in the hippocampus. Eftekharzadeh, B. Neuron 99, Eichenbaum, H. The hippocampus and declarative memory: cognitive mechanisms and neural codes. Elobeid, A. Altered proteins in the aging brain.

Evola, M. Oxidative stress impairs learning and memory in apoE knockout mice. Fang, E. Trends Mol. Fasolino, M. The crucial role of DNA Methylation and MeCP2 in neuronal function. Genes Feng, J. Dnmt1 and Dnmt3a maintain DNA methylation and regulate synaptic function in adult forebrain neurons. Foksinski, M.

Urinary excretion of DNA repair products correlates with metabolic rates as well as with maximum life spans of different mammalian species. Forster, M. Age-related losses of cognitive function and motor skills in mice are associated with oxidative protein damage in the brain.

Fraga, C. Fukui, K. Impairment of learning and memory in rats caused by oxidative stress and aging, and changes in antioxidative defense systems. Furukawa, A. Gallo, F. Immediate early genes, memory and psychiatric disorders: focus on c-Fos, Egr1 and Arc. Gu, X. Oxidative stress induces DNA demethylation and histone acetylation in SH-SY5Y cells: potential epigenetic mechanisms in gene transcription in Aβ production.

Halliwell, B. Reactive oxygen species and the central nervous system. Free Radicals in Biology and Medicine. Oxford: Clarendon Press. Hamilton, M. A reliable assessment of 8-oxodeoxyguanosine levels in nuclear and mitochondrial DNA using the sodium iodide method to isolate DNA.

Nucleic Acids Res. Harman, D. Aging: a theory based on free radical and radiation chemistry. Free radical theory of aging: effect of free radical reaction inhibitors on the mortality rate of male LAF1 mice. Hayashi, Y. Reverse of age-dependent memory impairment and mitochondrial DNA damage in microglia by an overexpression of human mitochondrial transcription factor a in mice.

Hindle, J. Age Ageing 39, — Hosseini, M. Protective effect of l-arginine against oxidative damage as a possible mechanism of its Bene.

cial properties on spatial learning in ovariectomized rats. Basic Clin. Hu, D. Aging-dependent alterations in synaptic plasticity and memory in mice that overexpress extracellular superoxide dismutase. Jessop, P. Hippocampal TET1 and TET2 expression and DNA hydroxymethylation are affected by physical exercise in aged mice.

Cell Dev. Jones, D. Redefining oxidative stress. Redox Signal. Kaas, G. TET1 Controls CNS 5-methylcytosine hydroxylation, Active DNA Demethylation, gene transcription, and memory formation.

Neuron 79, — Kamsler, A. Aged SOD overexpressing mice exhibit enhanced spatial memory while lacking Hippocampal neurogenesis.

Keller, J. Evidence of increased oxidative damage in subjects with mild cognitive impairment. Neurology 64, — Kilgore, M. Kinugawa, K. Aging-related episodic memory decline: are emotions the key?

Klungland, A. Accumulation of premutagenic DNA lesions in mice defective in removal of oxidative base damage. Kolarow, R. BDNF-induced nitric oxide signals in cultured rat hippocampal neurons: time course, mechanism of generation, and effect on neurotrophin secretion.

Kotambail, A. Epigenetics and human diseases. Kriaucionis, S. The nuclear DNA base 5-hydroxymethylcytosine is present in Purkinje neurons and the brain. Leal, N. Alterations in mitochondria-endoplasmic reticulum connectivity in human brain biopsies from idiopathic normal pressure hydrocephalus patients.

Acta Neuropathol. Levenson, J. Regulation of histone acetylation during memory formation in the hippocampus. Levine, B. Aging and autobiographical memory: dissociating episodic from semantic retrieval. Aging 17, — Lewandowska, J. DNA methylation in cancer development, diagnosis and therapy—multiple opportunities for genotoxic agents to act as methylome disruptors or remediators.

Mutagenesis 26, — Lezak, M. Neuropsychological Assessment , 5th Edn, Oxford: Oxford University Press. Lima-Cabello, E. An abnormal nitric oxide metabolism contributes to brain oxidative stress in the mouse model for the fragile X syndrome, a possible role in intellectual disability.

Lindahl, T. Instability and decay of the primary structure of DNA. Nature , — Rate of depurination of native deoxyribonucleic acid. Biochemistry 11, — Linnarsson, S. Learning Deficit in BDNF Mutant Mice. Liu, R. Love, S. Oxidative stress in brain ischemia.

Brain Pathol. Brain , — Lubin, F. Epigenetic regulation of BDNF gene transcription in the consolidation of fear memory. Manczak, M. Martins, I. Antimicrobial activity inactivation and toxic immune reactions induce Epilepsy in humans.

Single gene inactivation with implications to diabetes and multiple organ dysfunction syndrome. Epigenetics 03, 1—8.

Nutrition therapy regulates caffeine metabolism with relevance to NAFLD and induction of type 3 diabetes. Diabetes Metab. Massudi, H. Redox Rep. Mecocci, P. Alzheimer Dis. Child Neurol. Oxidative damage to mitochondrial DNA shows marked age-dependent increases in human brain.

Miller, C. Cortical DNA methylation maintains remote memory. Covalent modification of DNA regulates memory formation. Neuron 53, — Milne, J.

Therefore, to compensate for this problem, a stable compound is usually utilized to trap the radical and enable a radical to be detectable [ ]. Despite of great interest in EPR spectroscopy over years, one of the major reasons why it has not been commonly used is probably low sensitivity especially at the concentrations of free radicals typically found in the biological system [ ].

Further studies are needed to apply EPR to human clinical studies. Antioxidants are divided into endogenous or exogenous agents.

The human endogenous antioxidant molecules include various enzymes such as SOD, GPX and catalase as well as non-enzymatic molecules e. uric acid, GSH, and ascorbic acid , precursors of antioxidants e.

N-acetyl cystein and cofactors of antioxidants e. selenium and coenzyme Q 10 [ ]. The exogenous antioxidants could be natural e. N-acetyl cysteine, NAC or synthetic e. α-Lipoic Acid [ ]. The most commonly used antioxidants for clinical applications include vitamin E the important scavenger of lipid peroxidation in the brain , vitamin C intracellular reducing molecule , NAC acting as a precursor of GSH , and coenzyme Q10 transporter of electrons from complexes I and II to III in the ETC.

Although the initial results of the efficacy of antioxidants in the animal studies have been promising, the majority of the clinical trials in humans have shown negative results in terms of their efficacy for neurodegenerative diseases.

A summary of clinical studies for neurodegenerative diseases is presented in Table 1 [ , , , , , , , , , , , , , , , , ]. The following explanations may address why the current clinical trials have not yet found the potential antioxidants, which would effectively treat neurodegenerative diseasess.

First, antioxidant therapy could not decrease oxidative stress in patients with neurodegenerative diseases potentially due to insufficient dose of antioxidants, unsuitable timing for therapy, or inappropriate duration of treatments [ ].

On each related issue, the actual challenge could be how to evaluate the exact effects of antioxidants on the levels of a particular ROS at its proper action sites [ ]. It is also important to evaluate the magnitude of therapeutic effects of antioxidants on alterations in levels of a particular ROS at its presumptively proper action sites [ ].

In that sense, the development of biomarkers to better assess ROS is critical for the development of novel antioxidant therapeutic approach of neurodegenerative diseases.

The second point is that the oxidative damage may not be the primary cause, which contributes to the pathophysiology of the neurodegenerative diseases. An increase in oxidative damage could occur during the progression of disease, but it does not necessarily mean that it certainly causes the disease [ ].

If so, antioxidants would not be the appropriate target for the treatment of neurodegenerative diseases. In addition, oxidative stress may not be the only cause of the disease. It should be noted that other deleterious processes such as inflammation and excitotoxicity also could be involved in the pathogenesis of neurodegenerative disease [ ].

Therefore, it would be necessary to apply the combination of antioxidants with other drugs or multifunctional agents in treating neurodegenerative diseases. Third, it is plausible that one single antioxidant may not be sufficient to resist the oxidative damage since the oxidative stress is modulated by a complex system of endogenous and exogenous antioxidants.

In this regard, the combinatory approach of antioxidants would be necessary to be studied in the treatment of neurodegenerative diseases [ , ]. Fourth, the timing of antioxidant therapy might not be optimal in previous clinical trials.

Most trials have assessed the efficacy of antioxidants in patients with advanced AD or PD. Given that antioxidants may exert a prophylactic role in neurodegenerative disease, the earlier application of antioxidants, even before the onset of symptoms, may be effective [ , ].

The optimization of time and duration of antioxidant therapy would be necessary to be elucidated. Fifth, inter-individual differences in the levels of endogenous antioxidants may affect responses to antioxidant therapy [ ].

Before starting antioxidant treatment, it might be helpful to select participants who could be the potential responders such as those with low levels of endogenous antioxidants, rather than the probable non-responders with high or normal levels of endogenous antioxidants [ ].

The role of oxidative stress in the pathogenesis of neurodegenerative diseases has been well demonstrated in many preclinical and clinical studies. However, the benefit of antioxidant therapy for neurodegenerative diseases is still controversial in human, although the pre-clinical studies have shown promising results.

One of reasons for such discrepancy would be that there was no effective measurement of oxidative stress in the brain.

Unfortunately, peripheral biomarkers may not necessarily represent oxidative stress in the brain and changes in neuronal function. Therefore, proper central biomarkers for oxidative stress should be identified to detect objective benefits to the brain and find exact therapeutic targets in treating neurodegenerative diseases.

DPRCT: double-blind, placebo-controlled, randomized clinical trial, MAOI: monoamine oxidase inhibitor, ADCS-ADL: alzheimer's disease cooperative study-activities of daily living, MMSE: mini-mental status examination, ADAS-total: alzheimer's disease assessment scale-total score, ADAS-Cog: alzheimer's disease assessment scale-cognitive subcomponent, CGIC: clinical global impression of change, UPDRS: unified parkinson disease rating scale.

en menu. Articles Forthcoming Current Issue Archives Article Tools View Full Text Abstract Article as PDF Print this Article Pubmed PMC PubReader Export to Citation Email Alerts Open Access. Share this article on :. Stats or Metrics PMC SCOPUS View Download Crossref Article Review Article. The Role of Oxidative Stress in Neurodegenerative Diseases Geon Ha Kim 1,2 , Jieun E.

Received : August 20, ; Revised : September 14, ; Accepted : September 14, Types of reactive oxygen species ROS Oxygen is susceptible to radical formation due to two unpaired electrons present in the outer electron shell [ 6 ].

Mitochondrial ROS production The mitochondrion is the primary source of ROS production in the majority of cells. NADPH oxidases Nox Nox, a transmembrane enzyme complex, is known to be another important endogenous source of O 2 - production as the result of the catalyzing the electron transfer from NADPH to oxygen [ 19 , 20 ].

Xanthine oxidases XO XO and xanthine dehydrogenase XDH are inter-convertible forms of xanthine oxidoreductase [ 32 ]. ROS production in the endoplasmic reticulum The endoplasmic reticulum ER is the membrane-based intracellular organelle that is primarily related to protein folding and lipid biosynthesis [ 10 , 36 ].

ROS production in peroxisomes Peroxisomes are present in most eukaryotic cells and participate in multiple metabolic pathways including fatty acid oxidation, phospholipid biosynthesis, amino acid catabolism, and oxidative part of the pentose phosphate pathway [ 10 , 39 ].

Superoxide dismutase SOD SOD plays a significant role in catalyzing the breakdown of highly reactive O 2 - to less reactive H 2 O 2 and oxygen [ 33 ].

Glutathione peroxidases GPX GPX contains a family of multiple isoenzymes which catalyze the reduction of H 2 O 2 and lipid peroxides utilizing GSH as an electron donor [ 2 , 33 ].

Catalase Catalase is responsible for the conversion of H 2 O 2 to water and oxygen using either iron or manganese as a cofactor [ 2 , 33 , 43 ]. Peroxiredoxins PRX PRX are thiol-specific peroxidases that catalyze the reduction of H 2 O 2 as well as other organic hydroperoxides and peroxynitrite [ 33 , 44 , 45 ].

Glutathione GSH GSH, a tripeptide synthesized from glutamate, cysteine, and glycine, exerts protective function of cell survival against oxidative stress [ 2 , 33 ]. Vitamin E Vitamin E is a lipid-soluble antioxidant that can attenuate the effects of peroxide and protect against lipid peroxidation in cell membranes [ 2 , 33 ].

Vitamin C Vitamin C is a water-soluble antioxidant, which is involved in the removal of free radicals by electron transfer and also acts as a cofactor for antioxidant enzymes [ 3 , 33 ]. Physiological functions of ROS Low to moderate levels of ROS are critical in cellular signaling and pro-survival pathways [ 3 , 5 , 40 , 58 ].

Oxidative stress: excessive accumulation of ROS In a healthy condition, the production of ROS is balanced by various antioxidant systems [ 2 , 33 ]. Alzheimer's disease Alzheimer's disease AD , as one of the most common neurodegenerative diseases, is characterized by progressive neuronal loss and accumulation of proteins including extracellular amyloid plaques Aβ and intracellular tau tangles neurofibrillary tangles, NFT [ 70 ].

Parkinson's disease Parkinson's disease PD is a neurodegenerative disorder characterized by selective neuronal loss of dopaminergic DA neurons in the substantia nigra pars compacta SNc and decreased DA levels in the nigrostriatal DA pathway in the brain [ 85 , 86 ].

Measurement of oxidative stress in peripheral blood Since oxidative stress may be a common pathophysiological mechanism underlying various neurodegenerative diseases, several surrogate markers for oxidative stress or antioxidant activity, including circulating lipid peroxides, GSH, and vitamins C and E, have been assessed in peripheral blood [ 69 , 95 , 96 , 97 , 98 ].

Magnetic Resonance Spectroscopy Glutathione GSH GSH is currently the only antioxidant which can be measured using 1 H magnetic resonance spectroscopy MRS [ ]. Vitamin C Ascorbic acid The concentration of vitamin C is approximately 1.

Positron Emission Tomography [ 62 Cu] diacetyl-bis N 4 -methylthiosemicarbazone [ 62 Cu] ATSM [ 62 Cu] diacetyl-bis N 4 -methylthiosemicarbazone [ 62 Cu] ATSM is a radiotracer for positron emission tomography PET that can measure intracellular over-reductive state [ ]. Electron paramagnetic resonance EPR spectroscopy EPR spectroscopy has been considered as one of possible methods to detect and characterize the radicals in vivo [ ].

Clinical studies with antioxidant therapy in neurodegenerative diseases Antioxidants are divided into endogenous or exogenous agents. Possible reasons for little efficacy of antioxidants in treating neurodegenerative diseases The following explanations may address why the current clinical trials have not yet found the potential antioxidants, which would effectively treat neurodegenerative diseasess.

Common reactive oxygen species ROS. The consecutive reduction of oxygen through adding electrons cause the formation of a variety of ROS, which include superoxide O 2 - , hydroxyl radical ·OH , hydroxyl ion OH - and hydrogen peroxide H 2 O 2.

The red dot indicates an unpaired electron. Generation of ROS. The superoxide O 2 - is generated from O 2 as a by-product of respiratory chain complex in the mitochondria or by NADPH oxidase. By superoxide dismutase SOD , the superoxide O 2 - can be transformed into hydrogen peroxide H 2 O 2 , which can be further transformed to a number of other ROS such as hydroxyl radicals ·OH and hydroxyl anions OH -.

Table 1 A summary of antioxidants in clinical studies for neurodegenerative diseases DPRCT: double-blind, placebo-controlled, randomized clinical trial, MAOI: monoamine oxidase inhibitor, ADCS-ADL: alzheimer's disease cooperative study-activities of daily living, MMSE: mini-mental status examination, ADAS-total: alzheimer's disease assessment scale-total score, ADAS-Cog: alzheimer's disease assessment scale-cognitive subcomponent, CGIC: clinical global impression of change, UPDRS: unified parkinson disease rating scale.

Lin MT, Beal MF. Mitochondrial dysfunction and oxidative stress in neurodegenerative diseases. Nature ; Gandhi S, Abramov AY. Mechanism of oxidative stress in neurodegeneration. Oxid Med Cell Longev ; Song P, Zou MH. In: Wang H, Patterson C. Atherosclerosis: risks, mechanisms, and therapies.

Federico A, Cardaioli E, Da Pozzo P, Formichi P, Gallus GN, Radi E. Mitochondria, oxidative stress and neurodegeneration. J Neurol Sci ; Patten DA, Germain M, Kelly MA, Slack RS.

Reactive oxygen species: stuck in the middle of neurodegeneration. J Alzheimers Dis ;SS Held P. An introduction to reactive oxygen species: measurement of ROS in cells white paper.

BioTek Instruments, Inc. Bolisetty S, Jaimes EA. Mitochondria and reactive oxygen species: physiology and pathophysiology. Int J Mol Sci ; Halliwell B. Oxidative stress and neurodegeneration: where are we now?. J Neurochem ; Zorov DB, Juhaszova M, Sollott SJ.

Mitochondrial reactive oxygen species ROS and ROS-induced ROS release. Physiol Rev ; Mani S. In: Rani V, Yadav UC. Free radicals in human health and disease.

New Delhi: Springer, ; Orrenius S. Reactive oxygen species in mitochondria-mediated cell death. Drug Metab Rev ; Widlansky ME, Gutterman DD. Regulation of endothelial function by mitochondrial reactive oxygen species.

Antioxid Redox Signal ; Cadenas E, Davies KJ. Mitochondrial free radical generation, oxidative stress, and aging. Free Radic Biol Med ; Mancuso M, Coppede F, Migliore L, Siciliano G, Murri L.

Mitochondrial dysfunction, oxidative stress and neurodegeneration. J Alzheimers Dis ; Quinlan CL, Perevoshchikova IV, Hey-Mogensen M, Orr AL, Brand MD. Sites of reactive oxygen species generation by mitochondria oxidizing different substrates.

Redox Biol ; McLennan HR, Degli Esposti M. The contribution of mitochondrial respiratory complexes to the production of reactive oxygen species. J Bioenerg Biomembr ; Yankovskaya V, Horsefield R, Törnroth S, Luna-Chavez C, Miyoshi H, Léger C, Byrne B, Cecchini G, Iwata S.

Architecture of succinate dehydrogenase and reactive oxygen species generation. Science ; Turrens JF. Mitochondrial formation of reactive oxygen species. J Physiol ; Infanger DW, Sharma RV, Davisson RL.

NADPH oxidases of the brain: distribution, regulation, and function. Babior BM. NADPH oxidase. Curr Opin Immunol ; Lambeth JD. NOX enzymes and the biology of reactive oxygen. Nat Rev Immunol ; Regulation of NAD P H oxidases by AMPK in cardiovascular systems. Görlach A, Brandes RP, Nguyen K, Amidi M, Dehghani F, Busse R.

A gp91phox containing NADPH oxidase selectively expressed in endothelial cells is a major source of oxygen radical generation in the arterial wall.

Circ Res ; Bengtsson SH, Gulluyan LM, Dusting GJ, Drummond GR. Novel isoforms of NADPH oxidase in vascular physiology and pathophysiology. Clin Exp Pharmacol Physiol ; Wingler K, Wünsch S, Kreutz R, Rothermund L, Paul M, Schmidt HH.

Upregulation of the vascular NAD P H-oxidase isoforms Nox1 and Nox4 by the renin-angiotensin system in vitro and in vivo. Van Buul JD, Fernandez-Borja M, Anthony EC, Hordijk PL. Expression and localization of NOX2 and NOX4 in primary human endothelial cells.

Clempus RE, Sorescu D, Dikalova AE, Pounkova L, Jo P, Sorescu GP, Schmidt HH, Lassègue B, Griendling KK. Nox4 is required for maintenance of the differentiated vascular smooth muscle cell phenotype.

Arterioscler Thromb Vasc Biol ; Ellmark SH, Dusting GJ, Fui MN, Guzzo-Pernell N, Drummond GR. The contribution of Nox4 to NADPH oxidase activity in mouse vascular smooth muscle.

Cardiovasc Res ; Bedard K, Krause KH. The NOX family of ROS-generating NADPH oxidases: physiology and pathophysiology. Gordillo G, Fang H, Park H, Roy S. Noxdependent nuclear H2O2 drives DNA oxidation resulting in 8-OHdG as urinary biomarker and hemangioendothelioma formation.

Dikalov SI, Dikalova AE, Bikineyeva AT, Schmidt HH, Harrison DG, Griendling KK. Distinct roles of Nox1 and Nox4 in basal and angiotensin II-stimulated superoxide and hydrogen peroxide production.

Abramov AY, Scorziello A, Duchen MR. Three distinct mechanisms generate oxygen free radicals in neurons and contribute to cell death during anoxia and reoxygenation. J Neurosci ; Dasuri K, Zhang L, Keller JN. Oxidative stress, neurodegeneration, and the balance of protein degradation and protein synthesis.

Harrison R. Structure and function of xanthine oxidoreductase: where are we now?. Physiological roles of xanthine oxidoreductase. Bhandary B, Marahatta A, Kim HR, Chae HJ.

An involvement of oxidative stress in endoplasmic reticulum stress and its associated diseases. Higa A, Chevet E. Redox signaling loops in the unfolded protein response.

Cell Signal ; Malhotra JD, Kaufman RJ. Endoplasmic reticulum stress and oxidative stress: a vicious cycle or a double-edged sword?. Schrader M, Fahimi HD. Peroxisomes and oxidative stress.

Biochim Biophys Acta ; Valko M, Leibfritz D, Moncol J, Cronin MT, Mazur M, Telser J. Free radicals and antioxidants in normal physiological functions and human disease.

Int J Biochem Cell Biol ; Power JH, Blumbergs PC. Cellular glutathione peroxidase in human brain: cellular distribution, and its potential role in the degradation of Lewy bodies in Parkinson's disease and dementia with Lewy bodies. Acta Neuropathol ; Brigelius-Flohé R, Maiorino M. Glutathione peroxidases.

Dröge W. Free radicals in the physiological control of cell function. Espinosa-Diez C, Miguel V, Mennerich D, Kietzmann T, Sánchez-Pérez P, Cadenas S, Lamas S.

Antioxidant responses and cellular adjustments to oxidative stress. Wood ZA, Schröder E, Robin Harris J, Poole LB. Structure, mechanism and regulation of peroxiredoxins. Trends Biochem Sci ; Oberley TD, Verwiebe E, Zhong W, Kang SW, Rhee SG.

Localization of the thioredoxin system in normal rat kidney. Seo MS, Kang SW, Kim K, Baines IC, Lee TH, Rhee SG. Identification of a new type of mammalian peroxiredoxin that forms an intramolecular disulfide as a reaction intermediate. J Biol Chem ; Hall A, Nelson K, Poole LB, Karplus PA. Structure-based insights into the catalytic power and conformational dexterity of peroxiredoxins.

Winterbourn CC, Metodiewa D. The reaction of superoxide with reduced glutathione. Arch Biochem Biophys ; Winterbourn CC. Reconciling the chemistry and biology of reactive oxygen species. Nat Chem Biol ; Thus, the mitochondria are both a source and a target of toxic ROS. Mitochondrial dysfunction and oxidative metabolism may play an important role in the pathogenesis of AD and other neurodegenerative diseases see Beal 3 for review.

Reduced cytochrome oxidase activity and messenger RNA levels have been found in autopsied brains of patients with AD. Using cybrid techniques, researchers have shown that AD cytochrome oxidase defects can be transferred into cybrid cell lines that demonstrate increased cytosolic calcium concentrations and an increase in free radical production.

Increased lipid peroxidation occurs in the brain in AD and is most prominent where degenerative changes are most pronounced. Decreases in polyunsaturated fatty acids, primarily arachidonic and docosahexaenoic acids, accompany lipid peroxidation in AD.

Oxidation of polyunsaturated fatty acids produces aldehydes, one of the most important of which is 4-hydroxynonenal HNE , a highly reactive cytotoxic substance capable of inhibiting glycolysis, nucleic acid and protein synthesis, and degrading proteins. Four-hydroxynonenal levels are increased in autopsied specimens from multiple brain regions and in the cerebrospinal fluid CSF in subjects with AD, and HNE adducts are present in NFTs.

Four-hydroxynonenal causes degeneration and death of cultured hippocampal neurons by impairing ion-motive adenosine triphosphatase activity and disrupting calcium homeostasis. Four-hydroxynonenal impairs glucose and glutamate transport and is capable of inducing apoptosis in cultured neurons.

Administration of HNE into the basal forebrain of rats causes damage to cholinergic neurons, diminished choline acetyltransferase, and impaired visuospatial memory. The F 2 -isoprostanes are prostaglandin-like compounds that are formed nonenzymatically by free radical—induced oxidation of arachidonic acid.

Oxidation of docosahexaenoic acid forms F 4 -neuroprostanes. F 2 -isoprostanes are elevated in postmortem ventricular CSF of subjects with AD, 8 and in the lumbar CSF from living patients with probable AD, but not in the CSF from living patients with amyotrophic lateral sclerosis.

This suggests that these quantifiable markers of brain lipid peroxidation potentially could be used to assess the efficacy of therapeutic agents to decrease lipid peroxidation in AD. The oxidation of proteins by free radicals may also play a meaningful role in AD.

Hydrazide-reactive protein carbonyl is a general assay of oxidative damage to protein. Several studies demonstrate an increase in protein carbonyls in multiple brain regions in subjects with AD and in their NFTs. Two enzymes that are especially sensitive to oxidative modification are glutamine synthetase and creatine kinase, both of which are markedly diminished in the brains of subjects with AD.

Oxidative alterations in glutamine synthetase could cause alteration of glutamate concentrations and enhance excitotoxicity, whereas oxidative impairment of creatine kinase could cause diminished energy metabolism in AD. Pathologic aggregation of proteins into fibrils is a characteristic of AD.

Oxidative modifications can cause crosslinking of covalent bonds of proteins leading to fibril formation and insolubility. Neurofibrillary tangles are characterized by the aggregation and hyperphosphorylation of tau proteins into paired helical filaments.

Phosphorylation is linked to oxidation through the microtubule-associated protein kinase pathway and through the activation of the transcription factor NFκB, thus potentially linking oxidation to the hyperphosphorylation of tau proteins. Oxidation of cysteine in tau protein controls the in vitro assembly of paired helical filaments.

The role of oxidation damage in NFT formation is supported by the presence of protein carbonyls, nitrotyrosine a marker of the potent radical peroxynitrite , HNE, acrolein another highly reactive aldehyde product of lipid peroxidation , advanced glycation end products AGE , and hemeoxygenase-1 an antioxidant enzyme in NFTs.

Oxidation of DNA can produce strand breaks, sister chromatid exchange, DNA-protein crosslinking, and base modifications. The DNA damage accumulating in nondividing mammalian cells may play a major role in aging-associated changes.

Several studies demonstrate an increase in oxidative DNA damage in the brains of subjects with AD see Gabbita et al 11 for review. Elevations of 5-hydroxyuracil, 8-hydroxyadenine, and 5-hydroxycytosine levels also have been found in nuclear brain fractions in subjects with AD.

The pattern of damage to multiple bases is most likely due to hydroxyl radical attack on DNA. Elevations of 8-OHdG levels in intact DNA have been described in the CSF of patients with AD, along with a decrease in free 8-OHdG, representing the repair product, suggesting that there is a double insult of increased DNA damage and deficiencies in repair mechanisms responsible for removal of oxidized bases in AD.

The importance of finding increased products of oxidation in the CSF of patients with in AD HNE, F 2 -isoprostanes, F 4 -neuroprostanes, 8-OHdG deserves further study.

Perhaps, coupled with the elevated tau protein levels and decreased levels of βA peptides in AD CSF, 13 they could possibly be used to improve the diagnostic accuracy of AD. Advanced glycation end products are posttranslational modifications of proteins that are formed when the amino group of proteins reacts nonenzymatically with monosaccharides, and may play a role in AD that is linked to oxidative modifications of βA peptides and tau.

β-Amyloid peptide binds to the receptors for AGE and generates ROS, activating νFκβ, which induces expression of macrophage colony-stimulating factor, enhancing proliferation of microglia. Activated microglia are capable of producing the superoxide radical and nitric oxide.

Tau and AGE antigens are localized in NFTs, and glycated tau added to neuroblastoma cells in cultures induces lipid peroxidation. Recent evidence suggests that methionine may act as an antioxidant defense molecule in proteins by its ability to scavenge oxidants and in the process undergo oxidation to form methionine sulfoxide.

The enzyme methionine sulfoxide reductase reverses methionine sulfoxide back to methionine. Our recent study shows a statistically significant decline in methionine sulfoxide reductase in postmortem brain specimens from subjects with AD, 15 which may contribute to an increase in protein oxidation in the AD brain.

Data from cell culture and animal experiments by Mattson 16 demonstrate that oxidative stress and dysregulation of calcium can damage neurons, which indicates a role for oxidative stress in the pathogenesis of AD.

Exposure of cultured neurons to βA peptides causes an increase in oxyradical formation and radical-mediated damage to membrane lipids and proteins. β-Amyloid—induced neuron death in vitro is attenuated by antioxidants such as vitamin E and glutathione.

β-Amyloid peptides are capable of spontaneously forming oxygen radicals that damage enzymes. They also generate radicals through interaction with iron and zinc, both of which are increased in the brain of subjects with AD. Familial, early-onset, autosomal-dominant AD is associated with mutations in the presenilin genes 1 and 2 and the amyloid precursor protein.

Experimental studies using cultured cells and transgenic mice expressing presenilin gene 1 mutations have yielded considerable progress in understanding the pathogenetic mechanisms of presenilin mutations.

This causes an apoptotic death of neurons that can be prevented by vitamin E and glutathione. Studies of transgenic mice and cultured neurons expressing the amyloid precursor protein mutations suggest that these mutations also lead to an increased production of free radicals in neurons.

Transgenic mice overexpressing the amyloid precursor protein mutation demonstrate HNE and hemeoxygenase-1 around βA peptide deposits, and iron and pentosidine an AGE in the center of βA deposits, indicating an association between oxidative stress and βA deposition.

Meta-analysis findings from 17 epidemiologic studies suggest that nonsteroidal anti-inflammatory drugs play a protective role against AD. Like free radicals, antioxidants come from several different sources.

Cells naturally produce antioxidants such as glutathione as it works on a cellular level. Foods such as fruits and vegetables provide many essential antioxidants in the form of vitamins and minerals that the body cannot create on its own.

Effects of oxidative stress. The effects of oxidative stress vary and are not always harmful. For example, oxidative stress.

that results from physical activity may have beneficial, regulatory effects on the body. Exercise increases free radical formation, which can cause temporary oxidative stress in the muscles.

Free radicals formed during physical activity regulate tissue growth and stimulate the production of antioxidants. Mild oxidative stress may also protect the body from infection and diseases.

This can contribute to aging and may play an important role in the development of a range of mild to severe conditions. Chronic inflammation. Inflammation is part of the complex biological response of body tissues to harmful stimuli, such as pathogens , damaged cells, or irritants, and is a protective response involving immune cells , blood vessels , a nd molecular mediators.

The function of inflammation is to eliminate the initial cause of cell injury, clear out necrotic cells and tissues damaged from the original insult and the inflammatory process, and initiate tissue repair.

A series of biochemical events propagates and matures the inflammatory response, involving the local vascular system , the immune system , and various cells within the injured tissue.

Prolonged inflammation, known as chronic inflammation , leads to a progressive shift in the type of cells present at the site of inflammation by simultaneous destruction and healing of t he tissue from the inflammatory process.

Chronic inflammation due to oxidative stress may lead to severe conditions and has been attributed directly or indirectly to over disease states.

Neurodegenerative diseases. The effects of oxidative stress may contribute to several neurodegenerative conditions and the acceleration of the aging process which can lead to loss of memory issues, cognitive function decline and many more issues.

The brain is particularly vulnerable to oxidative stress because brain cells require a substantial amount of oxygen. Brain cells use oxygen to perform intense metabolic activities that generate free radicals.

These free radicals help support brain cell growth, neuroplasticity, and cognitive functioning. During oxidative stress, excess free radicals can damage structures inside brain cells and even cause cell death, which may increase the risk of neurodegenerative conditions.

Oxidative stress also alters essential proteins, such as amyloid-beta peptides which can lead to neurodegenerative conditions.