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Reductive Reprogramming: A Not-So-Radical Hypothesis of Neurodegeneration Linking Redox Perturbations to Neuroinflammation and Excitotoxicity

Abstract

Free radical-mediated oxidative stress, neuroinflammation, and excitotoxicity have long been considered insults relevant to the progression of Alzheimer’s disease and other aging-related neurodegenerative disorders (NDD). Among these phenomena, the significance of oxidative stress and, more generally, redox perturbations, for NDD remain ill-defined and unsubstantiated. Here, I argue that (i) free radical-mediated oxidations of biomolecules can be dissociated from the progression of NDD, (ii) oxidative stress fails as a descriptor of cellular redox states under conditions relevant to disease, and (iii) aberrant upregulation of compensatory reducing activities in neural cells, resulting in reductive shifts in thiol-based redox potentials, may be an overlooked and paradoxical contributor to disease progression. In particular, I summarize evidence which supports the view that reductive shifts in the extracellular space can occur in response to oxidant and inflammatory signals and that these have the potential to reduce putative regulatory disulfide bonds in exofacial domains of the N-methyl-d-aspartate receptor, leading potentially to aberrant increases in neuronal excitability and, if sustained, excitotoxicity. The novel reductive reprogramming hypothesis of neurodegeneration presented here provides an alternative view of redox perturbations in NDD and links these to both neuroinflammation and excitotoxicity.

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Abbreviations

AD:

Alzheimer’s disease

ALS:

Amyotrophic lateral sclerosis

BACE1:

β-Secretase 1

DTT:

Dithiothreitol

Grx:

Glutaredoxin

GSH:

Reduced glutathione

GSSG:

Oxidized glutathione

IL-β:

Interleukin 1-β

LPS:

Lipopolysaccharide

NDD:

Neurodegenerative disease

NMDA:

N-methyl-d-aspartate

PD:

Parkinson’s disease

Prx:

Peroxiredoxin

RNOS:

Reactive nitrogen oxide species

ROS:

Reactive oxygen species

SOD-1:

Superoxide dismutase-1

TNFalpha:

Tumor necrosis factor-α

Trx:

Thioredoxin

TrxR:

Thioredoxin reductase

Txnip:

Thioredoxin-interacting protein

References

  • Adams JD Jr, Klaidman LK, Odunze IN, Shen HC, Miller CA (1991) Alzheimer’s and Parkinson’s disease. Brain levels of glutathione, glutathione disulfide, and vitamin E. Mol Chem Neuropathol 14:213–226

    Article  CAS  PubMed  Google Scholar 

  • Adimora NJ, Jones DP, Kemp ML (2010) A model of redox kinetics implicates the thiol proteome in cellular hydrogen peroxide responses. Antioxid Redox Signal 13:731–743

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Aizenman E, Lipton SA, Loring RH (1989) Selective modulation of NMDA responses by reduction and oxidation. Neuron 2:1257–1263

    Article  CAS  PubMed  Google Scholar 

  • Aksenov MY, Markesbery WR (2001) Changes in thiol content and expression of glutathione redox system genes in the hippocampus and cerebellum in Alzheimer’s disease. Neurosci Lett 302:141–145

    Article  CAS  PubMed  Google Scholar 

  • Alam ZI, Jenner A, Daniel SE, Lees AJ, Cairns N, Marsden CD, Jenner P, Halliwell B (1997) Oxidative DNA damage in the parkinsonian brain: an apparent selective increase in 8-hydroxyguanine levels in substantia nigra. J Neurochem 69:1196–1203

    Article  CAS  PubMed  Google Scholar 

  • Armstrong RA, Lantos PL, Cairns NJ (2005) Overlap between neurodegenerative disorders. Neuropathology 25:111–124

    Article  PubMed  Google Scholar 

  • Arner ES, Holmgren A (2000) Physiological functions of thioredoxin and thioredoxin reductase. Eur J Biochem 267:6102–6109

    Article  CAS  PubMed  Google Scholar 

  • Banerjee R (2012) Redox outside the box: linking extracellular redox remodeling with intracellular redox metabolism. J Biol Chem 287:4397–4402

    Article  CAS  PubMed  Google Scholar 

  • Baxter PS, Hardingham GE (2016) Adaptive regulation of the brain’s antioxidant defences by neurons and astrocytes. Free Rad Biol Med 100:147–152

    Article  CAS  PubMed  Google Scholar 

  • Baxter PS, Bell KFS, Hasel P, Kaindl AM, Fricker M, Thomson D, Cregan SP, Gillingwater TH, Hardingham GE (2015) Synaptic NMDA receptor activity is coupled to the transcriptional control of the glutathione system. Nat Commun 6:6761

    Article  CAS  PubMed  Google Scholar 

  • Beer SM, Taylor ER, Brown SE, Dahm CC, Costa NJ, Runswick MJ, Murphy MP (2004) Glutaredoxin 2 catalyzes the reversible oxidation and glutathionylation of mitochondrial membrane thiol proteins: Implications for mitochondrial redox regulation and antioxidant DEFENSE. J Biol Chem 279:47939–47951

    Article  CAS  PubMed  Google Scholar 

  • Benhar M, Forrester MT, Stamler JS (2009) Protein denitrosylation: enzymatic mechanisms and cellular functions. Nat Rev Mol Cell Biol 10:721–732

    Article  CAS  PubMed  Google Scholar 

  • Bergeron C (1995) Oxidative stress: its role in the pathogenesis of amyotrophic lateral sclerosis. J Neurol Sci 129(Suppl):81–84

    Article  PubMed  Google Scholar 

  • Bowling AC, Schulz JB, Brown RH Jr, Beal MF (1993) Superoxide dismutase activity, oxidative damage, and mitochondrial energy metabolism in familial and sporadic amyotrophic lateral sclerosis. J Neurochem 61:2322–2325

    Article  CAS  PubMed  Google Scholar 

  • Brennan AM, Suh SW, Won SJ, Narasimhan P, Kauppinen TM, Lee H, Edling Y, Chan PH, Swanson RA (2009) NADPH is the primary source of superoxide induced by NMDA receptor activation. Nat Neurosci 12:857–863

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Capper MJ, Wright GSA, Barbieri L, Luchinat E, Mercatelli E, McAlary L, Yerbury JJ, O’Neill P, Antonyuk SV, Banci L, Hasnain SS (2018) The cysteine-reactive molecule ebselen facilitates effective SOD1 maturation. Nat Commun 9:1693

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Casagrande S, Bonetto V, Fratelli M, Gianazza E, Eberini I, Massignan T, Salmona M, Chang G, Holmgren A, Ghezzi P (2002) Glutathionylation of human thioredoxin: a possible crosstalk between the glutathione and thioredoxin systems. Proc Natl Acad Sci USA 99:9745–9749

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Chin-Chan M, Navarro-Yepes J, Quintanilla-Vega B (2015) Environmental pollutants as risk factors for neurodegenerative disorders: Alzheimer and Parkinson diseases. Front Cell Neurosci 9:124

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Chowdhury T, Allen MF, Thorn TL, He Y, Hewett SJ (2018) Interleukin-1β protects neurons against oxidant-induced injury via the promotion of astrocyte glutathione production. Antioxidants 7:E100

    Article  CAS  PubMed  Google Scholar 

  • Cobley JN, Fiorello ML, Bailey DM (2018) 13 reasons why the brain is susceptible to oxidative stress. Redox Biol 15:490–503

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Cruz-Haces M, Tang J, Acosta G, Fernandez J, Shi R (2017) Pathological correlations between brain injury and chronic neurodegenerative diseases. Transl Neurodegen 6:20

    Article  CAS  Google Scholar 

  • Cumming RC, Schubert D (2005) Amyloid-beta induces disulfide bonding and aggregation of GAPDH in Alzheimer’s disease. FASEB J 19:2060–2062

    Article  CAS  PubMed  Google Scholar 

  • Cumming RC, Dargusch R, Fischer WH, Schubert D (2007) Increase in expression levels and resistance to sulfhydryl oxidation of peroxiredoxin isoforms in amyloid beta-resistant nerve cells. J Biol Chem 282:30523–30534

    Article  CAS  PubMed  Google Scholar 

  • Day AM, Brown JD, Taylor SR, Rand JD, Morgan BA, Veal EA (2012) Inactivation of a peroxiredoxin by hydrogen peroxide is critical for thioredoxin-mediated repair of oxidized proteins and cell survival. Mol Cell 45:398–408

    Article  CAS  PubMed  Google Scholar 

  • Dexter DT, Carter CJ, Wells FR, Javoy-Agid F, Agid Y, Lees A, Jenner P, Marsden CD (1989) Basal lipid peroxidation in substantia nigra is increased in Parkinson’s disease. J Neurochem 52:381–389

    Article  CAS  PubMed  Google Scholar 

  • Donelly DP, Dowgiallo MG, Salisbury JP, Aluri KC, Iyengar S, Chaudhari M, Mathew M, Miele I, Auclair JR, Lopez SA, Manetsch R, Agar JN (2018) Cyclic thiosulfinates and cyclic disulfides selectively cross-link thiols while avoiding modification of lone thiols. J Am Chem Soc 140:7377–7380

    Article  CAS  Google Scholar 

  • Dringen R (2000) Metabolism and functions of glutathione in the brain. Prog Neurobiol 62:649–671

    Article  CAS  PubMed  Google Scholar 

  • Du Y, Zhang H, Holmgren A (2012) Glutathione and glutaredoxin act as a backup of human thioredoxin reductase 1 to reduce thioredoxin 1 preventing cell death by aurothioglucose. J Biol Chem 287:38210–38219

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Du Y, Zhang H, Zhang X, Lu J, Holmgren A (2013) Thioredoxin 1 is inactivated due to oxidation induced by peroxiredoxin under oxidative stress and reactivated by the glutaredoxin system. J Biol Chem 288:32241–32247

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Dunn L, Allen GE, Mamais A, Ling H, Li A, Duberley KE, Hargreaves IP, Pope S, Holton JL, Lees A, Heales SJ, Bandopadhyay R (2014) Dysregulation of glucose metabolism is an early event in sporadic Parkinson’s disease. Neurobiol Aging 35:1111–1115

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Evans JR, Bielefeldt K (2000) Regulation of sodium currents through oxidation and reduction of thiol residues. Neuroscience 101:229–236

    Article  CAS  PubMed  Google Scholar 

  • Fass D (2012) Disulfide bonding in protein biophysics. Ann Rev Biophys 41:63–79

    Article  CAS  Google Scholar 

  • Fava A, Pirritano D, Plastino M, Cristiano D, Puccio G, Colica C, Ermio C, De Bartolo M, Mauro G, Bosco D (2013) The effect of lipoic acid therapy on cognitive functioning in patients with Alzheimer’s disease. J Neurodegen Dis 2013:454253

    Google Scholar 

  • Ferrante RJ, Browne SE, Shinobu LA, Bowling AC, Baik MJ, MacGarvey U, Kowall NW, Brown RH Jr, Beal MF (1997) Evidence of increased oxidative damage in both sporadic and familial amyotrophic lateral sclerosis. J Neurochem 69:2064–2074

    Article  CAS  PubMed  Google Scholar 

  • Filograna R, Beltramini M, Bubaccco L, Bisaglia M (2016) Anti-oxidants in Parkinson’s disease therapy: a critical point of view. Curr Neuropharmacol 14:260–271

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Foley TD, Kintner ME (2005) Brain PP2A is modified by thiol-disulfide exchange and intermolecular disulfide formation. Biochem Biophys Res Commun 330:1224–1229

    Article  CAS  PubMed  Google Scholar 

  • Foley TD, Armstrong JJ, Kupchak BR (2004) Identification and H2O2 sensitivity of the major constitutive MAPK phosphatase from rat brain. Biochem Biophys Res Commun 315:568–574

    Article  CAS  PubMed  Google Scholar 

  • Foley TD, Petro LA, Stredny CM, Coppa TM (2007) Oxidative inhibition of protein phosphatase 2A activity: role of catalytic subunit disulfides. Neurochem Res 32:1957–1964

    Article  CAS  PubMed  Google Scholar 

  • Foley TD, Stredny CN, Coppa TM, Gubbiotti MA (2010) An improved phenylarsine oxide-affinity method identifies triose phosphate isomerase as a candidate redox receptor protein. Neurochem Res 35:306–314

    Article  CAS  PubMed  Google Scholar 

  • Foley TD, Melideo SL, Healey AF, Lucas EJ, Koval JA (2011) Phenylarsine oxide binding reveals redox-active and potential regulatory vicinal thiols on the catalytic subunit of protein phosphatase 2A. Neurochem Res 36:232–240

    Article  CAS  PubMed  Google Scholar 

  • Foley TD, Clark AR, Stredny ES, Wierbowski BM (2012) SNAP-25 contains non-acylated thiol pairs than can form intrachain disulfide bonds: possible sites for redox modulation of neurotransmission. Cell Mol Neurobiol 32:201–208

    Article  CAS  PubMed  Google Scholar 

  • Foley TD, Cantarella KM, Gillespie PF, Stredny ES (2014) Protein vicinal thiol oxidations in the healthy brain: not so radical links between physiological oxidative stress and neural cell activities. Neurochem Res 39:2030–2039

    Article  CAS  PubMed  Google Scholar 

  • Foley TD, Katchur KM, Gillespie PF (2016) Disulfide stress targets modulators of excitotoxicity in otherwise healthy brains. Neurochem Res 41:2763–2770

    Article  CAS  PubMed  Google Scholar 

  • Foley TD, Koval KS, Gallagher AG, Olsen SH (2019) Potential widespread denitrosylation of brain proteins following prolonged restraint: proposed links between stress and central nervous system disease. Metab Brain Dis 34:183–189

    Article  CAS  PubMed  Google Scholar 

  • Gabbita SP, Lovell MA, Markesbery WR (1998) Increased nuclear DNA oxidation in the brain in Alzheimer’s disease. J Neurochem 71:2034–2040

    Article  CAS  PubMed  Google Scholar 

  • Galasko DR, Peskind E, Clark CM, Quinn JF, Ringman JM, Jicha GA, Cotman C, Montine TJ, Thomas RG, Aisen P (2012) Antioxidants for Alzheimer disease: a randomized clinical trial with cerebrospinal fluid biomarker measures. Arch Neurol 69:836–841

    Article  PubMed  PubMed Central  Google Scholar 

  • Garcia-Nogales P, Almeida A, Fernandez E, Medina JM, Bolanos JP (1999) Induction of glucose-6-phhosphate dehydrogenase by lipopolysaccharide contributes to preventing nitric oxide-mediated glutathione depletion in cultured rat astrocytes. J Neurochem 72:1750–1758

    Article  CAS  PubMed  Google Scholar 

  • Garcia-Nogales P, Almeida A, Bolanos JP (2003) Peroxynitrite protects neurons against nitric oxide-mediated apoptosis. A key role for glucose-6-phosphate dehydrogenase activity in neuroprotection. J Biol Chem 278:864–874

    Article  CAS  PubMed  Google Scholar 

  • Garcia-Santamarina S, Boronat S, Hidalgo E (2014) Reversible cysteine oxidation in hydrogen peroxide sensing and signal transduction. Biochemistry 53:2560–2580

    Article  CAS  PubMed  Google Scholar 

  • Garg SK, Banerjee R, Kipnis J (2008) Neuroprotective immunity: T-cell-derived glutamate endows astrocytes with a neuroprotective phenotype. J Immunol 180:3866–3873

    Article  CAS  PubMed  Google Scholar 

  • Garg SK, Vitvitsky V, Albin R, Banerjee R (2011) Astrocytic redox remodeling by amyloid beta peptide. Antioxid Redox Signal 14:2385–2397

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gavillet M, Allaman I, Magistretti PJ (2008) Modulation of astrocytic metabolic phenotype by proinflammatory cytokines. Glia 56:975–989

    Article  PubMed  Google Scholar 

  • Gil-Bea F, Akterin S, Persson T, Mateos L, Sandebring A, Avila-Carino J, Gutierrez-Rodriguez A, Sundstrom E, Holmgren A, Winblad B, Cedazo-Minguez A (2012) Thioredoxin-80 is a product of alpha-secretase cleavage that inhibits amyloid-beta aggregation and is decreased in Alzheimer’s disease brain. EMBO Mol Med 4:1097–1111

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gilmer LK, Ansari MA, Roberts KN, Scheff SW (2010) Age-related changes in mitochondrial respiration and oxidative damage in the cerebral cortex of the Fisher 344 rat. Mech Ageing Dev 131:133–143

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Giustarini D, Dalle-Donne I, Colombo R, Milzanii A, Rossi R (2008) Is ascorbate able to reduce disulfide bridges? A cautionary note. Nitric Oxide 19:252–258

    Article  CAS  PubMed  Google Scholar 

  • Go YM, Jones DP (2008) Redox compartmentalization in eukaryotic cells. Biochem Biophys Acta 1780:1273–1290

    Article  CAS  PubMed  Google Scholar 

  • Gould N, Doulias PT, Tenopoulou M, Raju K, Ischiropoulos H (2013) Regulation of protein function and signaling by reversible cysteine S-nitrosylation. J Biol Chem 288:26473–26479

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hager K, Marahrens A, Kenklies M, Riedere P, Munch G (2001) Alpha-lipoic acid as a new treatment option for Alzheimer type dementia. Arch Gerontol Geriatr 32:275–282

    Article  CAS  PubMed  Google Scholar 

  • Hager K, Kenklies M, McAfoose J, Engel J, Munch G (2007) Alpha-lipoic acid as a new treatment option for Alzheimer’s disease–a 48 months follow-up analysis. J Neural Transm Suppl 72:189–193

    CAS  Google Scholar 

  • Halvey PJ, Watson WH, Hansen JM, Go YM, Samali A, Jones DP (2005) Compartmental oxidation of thiol-disulphide redox couples during epidermal growth factor signaling. Biochem J 386:215–219

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hansen JM, Zhang H, Jones DP (2006) Differential oxidation of thioredoxin-1, thioredoxin-2, and glutathione by metal ions. Free Rad Biol Med 40:138–145

    Article  CAS  PubMed  Google Scholar 

  • Hansen RE, Roth D, Winther JR (2009) Quantifying the global cellular thiol-disulfide status. Proc Natl Acad Sci USA 106:422–427

    Article  PubMed  PubMed Central  Google Scholar 

  • Harman D (1956) Aging: a theory based on free radical and radiation chemistry. J Gerontol 11:298–300

    Article  CAS  PubMed  Google Scholar 

  • Hastings TG, Lewis DA, Zigmond MJ (1996) Role of oxidation in the neurotoxic effects of intrastriatal dopamine injections. Proc Natl Acad Sci USA 93:1956–1961

    Google Scholar 

  • Hattori F, Oikawa S (2007) Peroxiredoxins in the central nervous system. Subcell Biochem 44:357–374

    Article  PubMed  Google Scholar 

  • He Y, Jackman NA, Thorn TL, Vought VE, Hewett SJ (2015) Interleukin-1β protects astrocytes against oxidant-induce injury via an NF-κB-dependent upregulation of glutathione synthesis. Glia 63:1568–1580

    Article  PubMed  PubMed Central  Google Scholar 

  • Herin GA, Du S, Aizenman E (2001) The neuroprotective agent ebselen modifies NMDA receptor function via the redox modulatory site. J Neurochem 78:1307–1314

    Article  CAS  PubMed  Google Scholar 

  • Hirsch EC, Brandel JP, Galle P, Javoy-Agid F, Agid Y (1991) Iron and aluminum increase in the substantia nigra of patients with Parkinson’s disease: an X-ray microanalysis. J Neurochem 56:446–451

    Article  CAS  PubMed  Google Scholar 

  • Hoffman J, Haendeler J, Zeiher AM, Dimmeler S (2001) TNFalpha and oxLDL reduce protein S-nitrosylation in endothelial cells. J Biol Chem 276:41383–41387

    Article  Google Scholar 

  • Hongpaisan J, Winters CA, Andrews SB (2004) Strong calcium entry activates mitochondrial superoxide generation, upregulating kinase signaling in hippocampus neurons. J Neurosci 24:10878–10887

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hughes KC, Gao X, Kim IY, Rimm EB, Wang M, Weisskopf MG, Schwarzschild MA, Ascherio A (2016) Intake of antioxidant vitamins and risk of Parkinson’s disease. Mov Disord 31:1909–1914

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hwang J, Suh HW, Jeon YH, Hwang E, Nguyen LT, Yeom J, Lee SG, Lee C, Kim KJ, Kang BS, Jeong JO, Oh TK, Choi I, Lee JO, Kim MH (2014) The structural basis for the negative regulation of thioredoxin by thioredoxin-interacting protein. Nat Commun 5:2958

    Article  CAS  PubMed  Google Scholar 

  • Iwata-Ichikawa E, Kondo Y, Miyazaki I, Asanuma M, Ogawa N (1999) Glial cells protect neurons against oxidative stress via transcriptional upregulation of the glutathione synthesis. J Neurochem 72:2334–2344

    Article  CAS  PubMed  Google Scholar 

  • Janaky R, Varga V, Saransaari P, Oja SS (1993) Glutathione modulates the N-methyl-D-aspartate receptor-activated calcium influx into cultured rat cerebellar granule cells. Neurosci Lett 156:153–157

    Article  CAS  PubMed  Google Scholar 

  • Jeandel C, Nicolas MB, Dubois F, Nabet-Belleville F, Penin F, Cuny G (1989) Lipid peroxidation and free radical scavengers in Alzheimer’s disease. Gerontology 35:275–282

    Article  CAS  PubMed  Google Scholar 

  • Jones DP (2008) Radical-free biology of oxidative stress. Am J Physiol Cell Physiol 295:C849–C868

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kelleher ZT, Sha Y, Foster MW, Foster WM, Forrester MT, Marshall HE (2014) Thioredoxin-mediated denitrosylation regulates cytokine-induced nuclear factor κB (NF-κB) activation. J Biol Chem 289:3066–3072

    Article  CAS  PubMed  Google Scholar 

  • Kemp M, Go YM, Jones DP (2008) Nonequilibrium thermodynamics of thiol/disulfide redox systems: a perspective on redox systems biology. Free Rad Biol Med 44:921–937

    Article  CAS  PubMed  Google Scholar 

  • Khan MAI, Respondek M, Kjellstrom S, Deep S, Linse S, Akke M (2017) Cu/Zn Superoxide dismutase forms amyloid fibrils under near-physiological quiescent conditions: the roles of disulfide bonds and effects of denaturant. ACS Chem Neurosci 8:2019–2026

    Article  CAS  PubMed  Google Scholar 

  • Kwak YD, Wang R, Li JJ, Zhang YW, Xu H, Liao FF (2011) Differential regulation of BACE1 expression by oxidative and nitrosative signals. Mol Neurodegen 6:17

    Article  CAS  Google Scholar 

  • Levy DI, Sucher NJ, Lipton SA (1990) Redox modulation of NMDA receptor-mediated toxicity in mammalian central neurons. Neurosci Lett 110:291–296

    Article  CAS  PubMed  Google Scholar 

  • Lewerenz J, Maher P (2015) Chronic glutamate toxicity in neurodegenerative diseases-what is the evidence? Front Neurosci 9:469

    Article  PubMed  PubMed Central  Google Scholar 

  • Lovell MA, Ehmann WD, Butler SM, Markesbery WR (1995) Elevated thiobarbituric acid-reactive substances and antioxidant enzyme activity in the brain in Alzheimer’s disease. Neurology 45:1594–1601

    Article  CAS  PubMed  Google Scholar 

  • Lovell MA, Xie C, Gabbita SP, Markesbery WR (2000) Decreased thioredoxin and increased thioredoxin reductase levels in Alzheimer’s disease brain. Free Rad Biol Med 28:418–427

    Article  CAS  PubMed  Google Scholar 

  • Lu J, Holmgren A (2014) The thioredoxin antioxidant system. Free Rad Biol Med 66:75–87

    Article  CAS  PubMed  Google Scholar 

  • Lyras L, Cairns NJ, Jenner A, Jenner P, Halliwell B (1997) An assessment of oxidative damage to proteins, lipids, and DNA in brain from patients with Alzheimer’s disease. J Neurochem 68:2061–2069

    Article  CAS  PubMed  Google Scholar 

  • Madrigal JL, Hurtado O, Moro MA, Lizasoain I, Lorenzo P, Castrillo A, Bosca L, Leza JC (2002) The increase in TNF-alpha levels is implicated in NF-kappaB activation and inducible nitric oxide synthase expression in brain cortex after immobilization stress. Neuropsychopharmacol 26:155–163

    Article  CAS  PubMed  Google Scholar 

  • Mandal PK, Saharan S, Tripathi M, Murari G (2015) Brain glutathione levels–a novel biomarker for mild cognitive impairment and Alzheimer’s disease. Biol Psychiatry 78:702–710

    Article  CAS  PubMed  Google Scholar 

  • Marcus DL, Thomas C, Rodriguez C, Simberkoff K, Tsai JS, Strafaci JA, Freedman ML (1998) Increased peroxidation and reduced antioxidant enzyme activity in Alzheimer’s disease. Exp Neurol 150:40–44

    Article  CAS  PubMed  Google Scholar 

  • Markesbery WR (1997) Oxidative stress hypothesis in Alzheimer’s disease. Free Rad Biol Med 23:134–147

    Article  CAS  PubMed  Google Scholar 

  • Markesbery WR, Lovell MA (1998) Four-hydroxynonenal, a product of lipid peroxidation, is increased in the brain in Alzheimer’s disease. Neurobiol Aging 19:33–36

    Article  CAS  PubMed  Google Scholar 

  • Marshall HE, Hess DT, Stamler JS (2004) S-Nitrosylation: physiological regulation of NF-kappaB. Proc Natl Acad Sci 101:8841–8842

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Martins RN, Harper CG, Stokes GB, Masters CL (1986) Increased cerebral glucose-6-phosphate dehydrogenase activity in Alzheimer’s disease may reflect oxidative stress. J Neurochem 46:1042–1045

    Article  CAS  PubMed  Google Scholar 

  • Mathisen GA, Fonnum F, Paulsen RE (1996) Contributing mechanisms for cysteine excitotoxicity in cultured cerebellar granule cells. Neurochem Res 21:293–298

    Article  CAS  PubMed  Google Scholar 

  • McIntosh LJ, Trush MA, Troncoso JC (1997) Increased susceptibility of Alzheimer’s disease temporal cortex to oxygen free radical-mediated processes. Free Rad Biol Med 23:183–190

    Article  CAS  PubMed  Google Scholar 

  • McKenzie JA, Spielman LJ, Pointer CB, Lowry JR, Bajwa E, Lee CW, Klegeris A (2017) Neuroinflammtion as a common mechanism associated with the modifiable risk factors for Alzheimer’s and Parkinson’s diseases. Curr Aging Sci 10:158–176

    Article  CAS  PubMed  Google Scholar 

  • Mecocci P, Polidori MC (2012) Antioxidant clinical trials in mild cognitive impairment and Alzheimer’s disease. Biochim Biophys Acta 1822:631–638

    Article  CAS  PubMed  Google Scholar 

  • Mecocci P, MacGarvey U, Kaufman AE, Koontz D, Shoffner JM, Wallace DC, Beal MF (1993) Oxidative damage to mitochondrial DNA shows marked age-dependent increases in human brain. Ann Neurol 34:609–616

    Article  CAS  PubMed  Google Scholar 

  • Mecocci P, MacGarvey U, Beal MF (1994) Oxidative damage to mitochondrial DNA is increased in Alzheimer’s disease. Ann Neurol 36:747–751

    Article  CAS  PubMed  Google Scholar 

  • Monzani E, Nicolis S, Dell’Acqua S, Capucciati A, Bacchell C, Zucca F, Mosharov E, Sulzer D, Zecca L, Casella L (2018) Dopamine, oxidative stress and protein-quinone modifications in Parkinson’s and other neurodegenerative diseases. Angew Chem Int Ed Engl. https://doi.org/10.1002/anie.201811122

    Article  Google Scholar 

  • Moussaoui S, Obinu MC, Daniel N, Reibaud M, Blanchard V, Imperato A (2000) The antioxidant ebselen prevents neurotoxicity and clinical symptoms in a primate model of Parkinson’s disease. Exp Neurol 166:235–245

    Article  CAS  PubMed  Google Scholar 

  • Nakamura T, Prikhodko OA, Pirie E, Nagar S, Akhtar MW, Oh CK, McKercher SR, Ambasudhan R, Okamoto S, Lipton SA (2015) Aberrant protein S-nitrosylation contributes to the pathophysiology of neurodegenerative diseases. Neurobiol Dis 84:99–108

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Nelson MT, Woo J, Kang HW, Vitko I, Barrett PQ, Perez-Reyes E, Lee JH, Shins HS, Todorovic SM (2007) Reducing agents sensitize C-type nociceptors by relieving high-affinity zinc inhibition of T-type calcium channels. J Neurosci 27:8250–8260

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Nkabyo YS, Ziegler TR, Gu LH, Watson WH, Jones DP (2002) Glutathione and thioredoxin redox during differentiation in human colon epithelial (Caco-2) cells. Am J Physiol Gastrointest Liver Physiol 283:G1352–G1359

    Article  CAS  PubMed  Google Scholar 

  • Noda Y, McGeer PL, McGeer EG (1982) Lipid peroxides in brain during aging and vitamin E deficiency: possible relations to changes in neurotransmitter indices. Neurobiol Aging 3:173–178

    Article  CAS  PubMed  Google Scholar 

  • Nourooz-Zadeh J, Liu EH, Yhlen B, Anggard EE, Halliwell B (1999) F4-isoprostanes as specific marker of docosahexaenoic acid peroxidation in Alzheimer’s disease. J Neurochem 72:734–740

    Article  CAS  PubMed  Google Scholar 

  • Nunomura A, Perry G, Aliev G, Hirai K, Takeda A, Balraj EK, Jones PK, Ghanbari H, Wataya T, Shimohama S, Chiba S, Atwood CS, Petersen RB, Smith MA (2001) Oxidative damage is the earliest event in Alzheimer disease. J Neuropathol Exp Neurol 60:759–767

    Article  CAS  PubMed  Google Scholar 

  • Olanow CW (1990) Oxidation reactions in Parkinson’s disease. Neurology 40(Suppl 3):32–37

    Google Scholar 

  • Olney JW, Zorumski C, Price MT, Labruyere J (1990) L-Cysteine, a bicarbonate-sensitive endogenous excitotoxin. Science 248:596–599

    Article  CAS  PubMed  Google Scholar 

  • Orrell RW, Lane RJ, Ross M (2008) A systematic review of antioxidant treatment for amyotrophic lateral sclerosis/motor neuron disease. Amyotroph Lateral Scler 9:195–211

    Article  CAS  PubMed  Google Scholar 

  • Packer L, Cadenas E (2011) Lipoic acid: energy metabolism and redox regulation of transcription and cell signaling. J Clin Biochem Nutr 48:26–32

    Article  CAS  PubMed  Google Scholar 

  • Palmer AM (1999) The activity of the pentose phosphate pathway is increased in response to oxidative stress in Alzheimer’s disease. J Neural Transm 106:317–328

    Article  CAS  PubMed  Google Scholar 

  • Palmer AM, Burns MA (1994) Selective increase in lipid peroxidation in the inferior temporal cortex in Alzheimer’s disease. Brain Res 645:338–342

    Article  CAS  PubMed  Google Scholar 

  • Papadia S, Soriano FX, Leveille F, Martel MA, Dakin KA, Hansen HH, Kaindl A, Sifringer M, Fowler J, Stefovska V, McKenzie G, Craigon M, Corriveau R, Ghazal P, Horsburgh K, Yanker BA, Wyllie DJ, Ikonomidou C, Hardingham GE (2008) Synaptic NMDA receptor activity boosts intrinsic antioxidant defenses. Nat Neurosci 11:476–487

    Article  PubMed  PubMed Central  Google Scholar 

  • Persson T, Popescu BO, Cedazo-Minguez A (2014) Oxidative stress in Alzheimer’s disease: Why did antioxidant therapy fail? Oxid Med Cell Longev 2014:427318

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Peskin AV, Pace PE, Behring JB, Paton LN, Soethoudt M, Bachschmid MM, Winterbourn CC (2016) Glutathionylation of the active site cysteines of peroxiredoxin 2 and recycling by glutaredoxin. J Biol Chem 291:3053–3062

    Article  CAS  PubMed  Google Scholar 

  • Porciuncula LO, Rocha JB, Boeck CR, Vendite D, Souza DO (2001) Ebselen prevents excitotoxicity provoked by glutamate in rat cerebellar granule neurons. Neurosci Lett 299:217–220

    Article  CAS  PubMed  Google Scholar 

  • Pratico D, Lee MY, Trojanowski V, Rokach JQ, Fitzgerald J GA (1998) Increased F2-isoprostanes in Alzheimer’s disease: evidence for enhanced lipid peroxidation in vivo. FASEB J 12:1777–1783

    Article  CAS  PubMed  Google Scholar 

  • Rebrin I, Forster MJ, Sohal RS (2011) Association between life-span extension by caloric restriction and thiol redox state in two different strains of mice. Free Rad Biol Med 51:225–233

    Article  CAS  PubMed  Google Scholar 

  • Regan RF, Guo YP (1999) Potentiation of excitotoxic injury by high concentrations of extracellular glutathione. Neurosci 91:463–470

    Article  CAS  Google Scholar 

  • Ren X, Zou L, Lu J, Holmgren A (2018) Selenocysteine in mammalian thioredoxin reductase and application of ebselen as a therapeutic. Free Rad Biol Med 127:238–247

    Article  CAS  PubMed  Google Scholar 

  • Reynolds IJ, Rush EA, Aizenman E (1990) Reduction of NMDA receptors with dithiothreitol increases [3H]-ML-801 binding and NMDA-induced Ca2+ fluxes. Br J Pharmacol 101:178–182

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ruppersberg JP, Stocker M, Pongs O, Heinemann SH, Frank R, Koenen M (1991) Regulation of fast inactivation of cloned mammalian IK(A) channels by cysteine oxidation. Nature 352:711–714

    Article  CAS  PubMed  Google Scholar 

  • Russell RL, Siedlak SL, Raina AK, Bautista JM, Smith MA, Perry G (1999) Increased neuronal glucose-6-phosphate dehydrogenase and sulfhydryl levels indicate compensation to oxidative stress in Alzheimer disease. Arch Biochem Biophys 370:236–239

    Article  CAS  PubMed  Google Scholar 

  • Sayre LM, Zelasko DA, Harris PL, Perry G, Salomon RG, Smith RA (1997) 4-Hydroxynonenal-derived advanced lipid peroxidation end products are increased in Alzheimer’s disease. J Neurochem 68:2092–2097

    Article  CAS  PubMed  Google Scholar 

  • Schonhoff CM, Matsuoka M, Tummala H, Johnson MA, Estevez AG, Wu R, Kamaid A, Ricart KC, Hashimoto Y, Gaston B, MacDonald TL, Xu Z, Mannick JB (2006) S-nitrosothiol depletion in amyotrophic lateral sclerosis. Proc Natl Acad Sci 103:2404–2409

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Shelton MD, Chock PB, Mieyal JJ (2005) Glutaredoxin: role in reversible protein S-glutathionylation and regulation of redox signal transduction and protein translocation. Antioxid Redox Signal 7:348–366

    Article  CAS  PubMed  Google Scholar 

  • Sian J, Dexter DT, Lees AJ, Daniel S, Agid Y, Javoy-Agid F, Jenner P, Marsden CD (1994) Alterations in glutathione levels in Parkinson’s disease and other neurodegenerative disorders affecting basal ganglia. Ann Neurol 36:348–355

    Article  CAS  PubMed  Google Scholar 

  • Sies H (2015) Oxidative stress: a concept in redox biology and medicine. Redox Biol 4:180–183

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Smith MA, Perry G (1995) Free radical damage, iron, and Alzheimer’s disease. J Neurol Sci 134(Suppl):92–94

    Article  PubMed  Google Scholar 

  • Smith CD, Carney JM, Starke-Reed PE, Oliver CN, Stadtman ER, Floyd RA, Markesbery WR (1991) Excess brain protein oxidation and enzyme dysfunction in normal aging and in Alzheimer disease. Proc Natl Acad Sci 88:10540–10543

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Smith MA, Harris PL, Sayre LM, Perry G (1997a) Iron accumulation in Alzheimer disease is a source of redox-generated free radicals. Proc Natl Acad Sci USA 94:9866–9868

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Smith MA, Richey Harris PL, Sayre LM, Beckman JS, Perry G (1997b) Widespread peroxynitrite-mediated damage in Alzheimer’s disease. J Neurosci 17:2653–2657

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sohal RS, Orr WC (2012) The redox stress hypothesis of aging. Free Rad Biol Med 52:539–555

    Article  CAS  PubMed  Google Scholar 

  • Sonnen JA, Breitner JC, Lovell MA, Markesbery WR, Quinn JF, Montine TJ (2008) Free radical-mediated damage to brain in Alzheimer’s disease and its transgenic mouse models. Free Rad Biol Med 45:219–230

    Article  CAS  PubMed  Google Scholar 

  • Stargadt A, Swaab DF, Bossers K (2015) The storm before the quiet: neuronal hyperactivity and Aβ in the presymptomatic stages of Alzheimer’s disease. Neurobiol Aging 36:1–11

    Article  CAS  Google Scholar 

  • Stelle ML, Fuller S, Maczurek AF, Kersaitis C, Ooi L, Munch G (2013) Chronic inflammation alters production and release of glutathione and related thiols in human U373 astroglial cells. Cell Mol Biol 33:19–30

    Google Scholar 

  • Stephenson J, Nutma E, van der Valk P, Amor S (2018) Inflammation in CNS neurodegenerative disorders. Immunology 154:204–219

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Stocker S, Van Laer K, Mijuskovic A, Dick TP (2018) The conundrum of hydrogen peroxide signaling and the emerging role of peroxiredoxins as redox relay hubs. Antioxid Redox Signal 28:558–573

    Article  CAS  PubMed  Google Scholar 

  • Subbarao KV, Richardson JS, Ang LC (1990) Autopsy samples of Alzheimer’s cortex show increased peroxidation in vitro. J Neurochem 55:342–345

    Article  CAS  PubMed  Google Scholar 

  • Sucher NJ, Wong LA, Lipton SA (1990) Redox modulation of NMDA receptor-mediated Ca2+ flux in mammalian central neurons. Neuroreport 1:29–32

    Article  CAS  PubMed  Google Scholar 

  • Sullivan JM, Traynelis SF, Chen HS, Escobar W, Heinemann SF, Lipton SA (1994) Identification of two cysteine residues that are required for redox modulation of the NMDA subtype of glutamate receptor. Neuron 13:929–936

    Article  CAS  PubMed  Google Scholar 

  • Tan SX, Greetham D, Raeth S, Grant CM, Dawes IW, Perrone GG (2010) The thioredoxin-thioredoxin reductase system can function in vivo as an alternative system to reduce oxidized glutathione in Saccharomyces cerevisiae. J Biol Chem 285:6118–6126

    Article  CAS  PubMed  Google Scholar 

  • Tang LH, Aizenman E (1993a) Allosteric modulation of the NMDA receptor by dihydrolipoic and lipoic acid in rat cortical neurons in vitro. Neuron 11:857–863

    Article  CAS  PubMed  Google Scholar 

  • Tang LH, Aizenman E (1993b) The modulation of N-methyl-D-aspartate receptors by redox and alkylating reagents in rat cortical neurons in vitro. J Physiol 465:303–323

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Te Koppele JM, Lucassen PJ, Sakkee AN, Asten JG, Ravid R, Swaab DF, Van Bezooijen CF (1996) 8OHdG levels in brain do not indicate oxidative DNA damage in Alzheimer’s disease. Neurobiol Aging 17:819–826

    Article  CAS  PubMed  Google Scholar 

  • Verma M, Wills Z, Chu CT (2018) Excitatory dendritic mitochondrial calcium toxicity: Implications for Parkinson’s and other neurodegenerative diseases. Front Neurosci 12:523

    Article  PubMed  PubMed Central  Google Scholar 

  • Volicer L, Crino PB (1990) Involvement of free radicals in dementia of the Alzheimer type: a hypothesis. Neurobiol Aging 11:567–571

    Article  CAS  PubMed  Google Scholar 

  • Vyas S, Rodrigues AJ, Silva JM, Tronche F, Almeida OF, Sousa N, Sotiropoulos I (2016) Chronic stress and glucocorticoids: From neuronal plasticity to neurodegeneration. Neural Plast 2016:6391686

  • Wadham C, Parker A, Wang L, Xia P (2007) High glucose attenuates protein S-nitrosylation in endothelial cells: roles of oxidative stress. Diabetes 56:2715–2721

    Article  CAS  PubMed  Google Scholar 

  • Walker S, Ullman O, Stultz CM (2012) Using intramolecular disulfide bonds in tau to deduce structural features of aggregation-resistant conformations. J Biol Chem 287:9591–9600

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Weiduschat N, Mao X, Hupf J, Armstrong N, Kang G, Lange DJ, Mitsumoto H, Shungu DC (2014) Motor cortex glutathione deficit in ALS measured in vivo with the J-editing technique. Neurosci Lett 570:102–107

    Article  CAS  PubMed  Google Scholar 

  • Wolhuter K, Whitwell HJ, Switzer CH, Burgoyne JR, Timms JF, Eaton P (2018) Evidence against stable protein S-nitrosylation as a widespread mechanism of post-translational regulation. Mol Cell 69:438–450

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wood ZA, Schroder E, Robin Harris J, Poole LB (2003) Structure, mechanism, and regulation of peroxiredoxins. Trends Biochem Sci 28:32–40

    Article  CAS  PubMed  Google Scholar 

  • Xie Y, Tan Y, Zheng Y, Du X, Liu Q (2017) Ebselen ameliorates β-amyloid pathology, tau pathology, and cognitive impairment in triple-transgenic Alzheimer’s disease mice. J Biol Inorg Chem 22:851–865

    Article  CAS  PubMed  Google Scholar 

  • Yan Z, Garg SK, Kipnis J, Banerjee R (2009) Extracellular redox modulation by regulatory T cells. Nat Chem Biol 5:721–723

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yang KS, Kang SW, Woo HA, Hwang SC, Chae HZ, Kim K, Rhee SG (2002) Inactivation of human peroxiredoxin I during catalysis as the results of the oxidation of the catalytic cysteine to cysteine-sulfinic acid. J Biol Chem 277:38029–38036

    Article  CAS  PubMed  Google Scholar 

  • Zhao R, Masayasu H, Holmgren A (2002) Ebselen: a substrate for human thioredoxin reductase strongly stimulating its hydroperoxide reductase activity and a superfast thioredoxin oxidant. Proc Natl Acad Sci USA 99:8579–8584

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Foley, T.D. Reductive Reprogramming: A Not-So-Radical Hypothesis of Neurodegeneration Linking Redox Perturbations to Neuroinflammation and Excitotoxicity. Cell Mol Neurobiol 39, 577–590 (2019). https://doi.org/10.1007/s10571-019-00672-w

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Keywords

  • Excitotoxicity
  • Neurodegenerative disease
  • Neuroinflammation
  • Oxidative stress
  • Protein thiols
  • Redox signaling
  • Reductive stress