Skip to main content
PMC home page
Redox Report : Communications in Free Radical Research logoLink to Redox Report : Communications in Free Radical Research
. 2013 Jul 19;15(4):161–168. doi: 10.1179/174329210X12650506623645

Indoleamine 2,3-dioxygenase and 3-hydroxykynurenine modifications are found in the neuropathology of Alzheimer's disease

David J Bonda 1, Maneesh Mailankot 2, Jeremy G Stone 1, Matthew R Garrett 3, Magdalena Staniszewska 4, Rudy J Castellani 5, Sandra L Siedlak 1, Xiongwei Zhu 1, Hyoung-gon Lee 1, George Perry 6, Ram H Nagaraj 2, Mark A Smith 7
PMCID: PMC2956440  NIHMSID: NIHMS238740  PMID: 20663292

Abstract

Tryptophan metabolism, through the kynurenine pathway, produces neurotoxic intermediates that are implicated in the pathogenesis of Alzheimer's disease. In particular, oxidative stress via 3-hydroxykynurenine (3-HK) and its cleaved product 3-hydroxyanthranilic acid (3-HAA) significantly damages neuronal tissue and may potentially contribute to a cycle of neurodegeneration through consequent amyloid-β accumulation, glial activation, and up-regulation of the kynurenine pathway. To determine the role of the kynurenine pathway in eliciting and continuing oxidative stress within Alzheimer's diseased brains, we used immunocytochemical methods to show elevated levels of 3-HK modifications and the upstream, rate-limiting enzyme indoleamine 2,3-dioxygenase (IDO-1) in Alzheimer's diseased brains when compared to controls. Importantly, the association of IDO-1 with senile plaques was confirmed and, for the first time, IDO-1 was shown to be specifically localized in conjunction with neurofibrillary tangles. As senile plaques and neurofibrillary tangles are the pathological hallmarks of Alzheimer's disease, our study provides further evidence that the kynurenine pathway is involved with the destructive neurodegenerative pathway of Alzheimer's disease.

Keywords: ALZHEIMER'S DISEASE; AMYLOID-β; HYPERPHOSPHORYLATED TAU; INDOLEAMINE 2,3-DIOXYGENASE; KYNURENINE; KYNURENINE PATHWAY; QUINOLINIC ACID; TRYPTOPHAN

Full Text

The Full Text of this article is available as a PDF (468.7 KB).

References

  • 1.Beadle GW, Mitchell HK, Nyc JF. Kynurenine as an intermediate in the formation of nicotinic acid from tryptophane by neurospora. Proc Natl Acad Sci USA 1947; 33: 155–158. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 2.Takikawa O. Clinical aspects of indoleamine 2,3-dioxygenase (IDO)-initiated tryptophan metabolism: IDO is a target of drug discovery for various diseases. Int Congr Ser 2007; 1304: 290–297. [Google Scholar]
  • 3.Wolf H. Studies on tryptophan metabolism in man. Scand J Clin Lab Invest 1974; 136 (Suppl): 1-186. [Google Scholar]
  • 4.Dang Y, Dale WE, Brown OR. Comparative effects of oxygen on indoleamine 2,3-dioxygenase and tryptophan 2,3-dioxygenase of the kynurenine pathway. Free Radic Biol Med 2000; 28: 615–624. [DOI] [PubMed] [Google Scholar]
  • 5.Dang Y, Dale WE, Brown OR. Effects of oxygen on kynurenine-3-monooxygenase activity. Redox Rep 2000; 5: 81–84. [DOI] [PubMed] [Google Scholar]
  • 6.Dale WE, Dang Y, Brown OR. Tryptophan metabolism through the kynurenine pathway in rat brain and liver slices. Free Radic Biol Med 2000; 29: 191–198. [DOI] [PubMed] [Google Scholar]
  • 7.Thomas SR, Salahifar H, Mashima R, Hunt NH, Richardson DR, Stocker R. Antioxidants inhibit indoleamine 2,3-dioxygenase in IFN-gamma-activated human macrophages: posttranslational regulation by pyrrolidine dithiocarbamate. J Immunol 2001; 166: 6332–6340. [DOI] [PubMed] [Google Scholar]
  • 8.Taylor MW, Feng GS. Relationship between interferon-gamma, indoleamine 2,3-dioxygenase, and tryptophan catabolism. FASEB J 1991; 5: 2516–2522. [PubMed] [Google Scholar]
  • 9.Carlin JM, Ozaki Y, Byrne GI, Brown RR, Borden EC. Interferons and indoleamine 2,3-dioxygenase: role in antimicrobial and antitumor effects. Experientia 1989; 45: 535–541. [DOI] [PubMed] [Google Scholar]
  • 10.Dang Y, Xia C, Brown OR. Effects of oxygen on 3-hydroxyanthranilate oxidase of the kynurenine pathway. Free Radic Biol Med 1998; 25: 1033–1043. [DOI] [PubMed] [Google Scholar]
  • 11.Boehm DE, Vincent K, Brown OR. Oxygen and toxicity inhibition of amino acid biosynthesis. Nature 1976; 262: 418–420. [DOI] [PubMed] [Google Scholar]
  • 12.Braun JS, Sublett JE, Freyer D et al. Pneumococcal pneumolysin and H(2)0(2) mediate brain cell apoptosis during meningitis'. J Clin Invest 2002; 109: 19–27. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 13.Eastman CL, Guilarte TR. The role of hydrogen peroxide in the in vitro cytotoxicity of 3-hydroxykynurenine. Neurochem Res 1990; 15: 1101–1107. [DOI] [PubMed] [Google Scholar]
  • 14.Staniszewska MM, Nagaraj RH. 3-Hydroxykynurenine-mediated modification of human lens proteins: structure determination of a major modification using a monoclonal antibody. J Biol Chem 2005; 280: 22154–22164. [DOI] [PubMed] [Google Scholar]
  • 15.Amiridze N, Dang Y, Brown OR. Hydroxyl radicals detected via brain microdialysis in rats breathing air and during hyperbaric oxygen convulsions. Redox Rep 1999; 4: 165–170. [DOI] [PubMed] [Google Scholar]
  • 16.Dale WE, Dang Y, Amiridze N, Brown OR. Evidence that kynurenine pathway metabolites mediate hyperbaric oxygen-induced convulsions. Toxicol Lett 2000; 117: 37–43. [DOI] [PubMed] [Google Scholar]
  • 17.Brown OR, Lusiak-Draczynska B. Oxygen inactivation of quinolinate-producing and iron-requiring 3-hydroxyanthranilic acid oxidase: a role in hyperbaric oxygen-induced convulsions? Redox Rep 1995; 1: 383–385. [DOI] [PubMed] [Google Scholar]
  • 18.Klivenyi P, Toldi J, Vecsei L. Kynurenines in neurodegenerative disorders: therapeutic consideration. Adv Exp Med Biol 2004; 541: 169–183. [DOI] [PubMed] [Google Scholar]
  • 19.Schwarcz R, Kohler C. Differential vulnerability of central neurons of the rat to quinolinic acid. Neurosci Lett 1983; 38: 85–90. [DOI] [PubMed] [Google Scholar]
  • 20.Schwarcz R, Foster AC, French ED, Jr WO Whetsell, Kohler C. Excitotoxic models for neurodegenerative disorders. Life Sci 1984; 35: 19–32. [DOI] [PubMed] [Google Scholar]
  • 21.Stone TW, Perkins MN. Quinolinic acid: a potent endogenous excitant at amino acid receptors in CNS. Eur J Pharmacol 1981; 72: 411–412. [DOI] [PubMed] [Google Scholar]
  • 22.Guillemin GJ, Brew BJ. Implications of the kynurenine pathway and quinolinic acid in Alzheimer's disease. Redox Rep 2002; 7: 199–206. [DOI] [PubMed] [Google Scholar]
  • 23.Lim CK, Brew BJ, Guillemin GJ. Understanding the roles of the kynurenine pathway in multiple sclerosis progression. Int J Tryptophan Res 2010; 3: 1–11. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 24.Guillemin GJ, Kerr SJ, Brew BJ. Involvement of quinolinic acid in AIDS dementia complex. Neurotoxin Res 2005; 7: 103–123. [DOI] [PubMed] [Google Scholar]
  • 25.Nemeth H, Toldi J, Vecsei L. Role of kynurenines in the central and peripheral nervous systems. Curr Neurovasc Res 2005; 2: 249–260. [DOI] [PubMed] [Google Scholar]
  • 26.Stone TW. Kynurenines in the CNS: from endogenous obscurity to therapeutic importance. Prog Neurobiol 2001; 64: 185–218. [DOI] [PubMed] [Google Scholar]
  • 27.Stone TW, Mackay GM, Forrest CM, Clark CJ, Darlington LG. Tryptophan metabolites and brain disorders. Clin Chem Lab Med 2003; 41: 852–859. [DOI] [PubMed] [Google Scholar]
  • 28.Widner B, Leblhuber F, Walli J, Tilz GP, Demel U, Fuchs D. Tryptophan degradation and immune activation in Alzheimer's disease. J Neural Transm 2000; 107: 343–353. [DOI] [PubMed] [Google Scholar]
  • 29.Guillemin GJ, Brew BJ, Noonan CE, Takikawa O, Cullen KM. Indoleamine 2,3 dioxygenase and quinolinic acid immunoreactivity in Alzheimer's disease hippocampus. Neuropathol Appl Neurobiol 2005; 31: 395–404. [DOI] [PubMed] [Google Scholar]
  • 30.Smith MA. Alzheimer disease. Int Rev Neurobio11998; 42: 1-54. [DOI] [PubMed] [Google Scholar]
  • 31.Zhu X, Lee HG, Perry G, Smith MA. Alzheimer disease, the two-hit hypothesis: an update. Biochim Biophys Acta 2007; 1772: 494–502. [DOI] [PubMed] [Google Scholar]
  • 32.Kalaria RN. Microglia and Alzheimer's disease. Curr Opin Hematol 1999; 6: 15–24. [DOI] [PubMed] [Google Scholar]
  • 33.Shimohama S, Tanino H, Kawakami N et al. Activation of NADPH oxidase in Alzheimer's disease brains. Biochem Biophys Res Commun 2000; 273: 5–9. [DOI] [PubMed] [Google Scholar]
  • 34.Guillemin GJ, Smith DG, Smythe GA, Armati PJ, Brew BJ. Expression of the kynurenine pathway enzymes in human microglia and macrophages. Adv Exp Med Biol 2003; 527: 105–112. [DOI] [PubMed] [Google Scholar]
  • 35.Guillemin GJ, Kerr SJ, Smythe GA, Armati PJ, Brew BJ. Kynurenine pathway metabolism in human astrocytes. Adv Exp Med Biol 1999; 467: 125–131. [DOI] [PubMed] [Google Scholar]
  • 36.Guillemin GJ, Kerr SJ, Smythe GA et al. Kynurenine pathway metabolism in human astrocytes: a paradox for neuronal protection. J Neurochem 2001; 78: 842–853. [DOI] [PubMed] [Google Scholar]
  • 37.Ralunan A, Ting K, Cullen KM, Braidy N, Brew BJ, Guillemin GJ. The excitotoxin quinolinic acid induces tau phosphorylation in human neurons. PLoS One 2009; 4: e6344. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 38.Takashima A. Hyperphosphorylated tau is a cause of neuronal dysfunction in tauopathy. J Alzheimers Dis 2008; 14: 371–375. [DOI] [PubMed] [Google Scholar]
  • 39.Stemberger LA. Immunocytochemistry,3rd edn. New York: Wiley, 1986. [Google Scholar]
  • 40.Su B, Wang X, Drew KL, Perry G, Smith MA, Zhu X. Physiological regulation of tau phosphorylation during hibernation. J Neurochem 2008; 105: 2098–2108. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 41.Zhu X, Rottkamp CA, Boux H, Takeda A, Perry G, Smith MA. Activation of p38 kinase links tau phosphorylation, oxidative stress, and cell cycle-related events in Alzheimer disease. J Neuropathol Exp Neurol 2000; 59: 880–888. [DOI] [PubMed] [Google Scholar]
  • 42.Lee HG, Ogawa O, Zhu X et al. Aberrant expression of metabotropic glutamate receptor 2 in the vulnerable neurons of Alzheimer's disease. Acta Neuropathol (Ben) 2004; 107: 365–371. [DOI] [PubMed] [Google Scholar]
  • 43.Smith MA, Zhu X, Tabaton M et al. Increased iron and free radical generation in preclinical Alzheimer disease and mild cognitive impairment. J Alzheimers Dis 2010; 19: 363–372. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 44.Reddy VP, Zhu X, Perry G, Smith MA. Oxidative stress in diabetes and Alzheimer's disease. J Alzheimers Dis 2009; 16: 763–774. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 45.Zhu X, Su B, Wang X, Smith MA, Perry G. Causes of oxidative stress in Alzheimer disease. Cell Mol Life Sci 2007; 64: 2202–2210. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 46.Nunomura A, Perry G, Aliev G et al. Oxidative damage is the earliest event in Alzheimer disease. J Neuropathol Exp Neurol 2001; 60: 759–767. [DOI] [PubMed] [Google Scholar]
  • 47.Kontush A, Berndt C, Weber W et al. Amyloid-beta is an antioxidant for lipoproteins in cerebrospinal fluid and plasma. Free Radic Biol Med 2001; 30: 119–128. [DOI] [PubMed] [Google Scholar]
  • 48.Atwood CS, Moir RD, Huang X et al. Dramatic aggregation of Alzheimer abeta by Cu(II) is induced by conditions representing physiological acidosis. J Biol Chem 1998; 273: 12817–12826. [DOI] [PubMed] [Google Scholar]
  • 49.Masters CL, Simms G, Weinman NA, Multhaup G, McDonald BL, Beyreuther K. Amyloid plaque core protein in Alzheimer disease and Down syndrome. Proc Natl Acad Sci USA 1985; 82: 4245–4249. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 50.Smith MA, Richey Harris PL, Sayre LM, Beckman JS, Perry G. Widespread peroxynitrite-mediated damage in Alzheimer's disease. J Neurosci 1997; 17: 2653–2657. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 51.Kalaria RN. Microglia and Alzheimer's disease. Curr Opin Hematol 1999; 6: 15–24. [DOI] [PubMed] [Google Scholar]
  • 52.Braidy N, Grant R, Adams S, Brew BJ, Guillemin GJ. Mechanism for quinolinic acid cytotoxicity in human astrocytes and neurons. Neurotox Res 2009; 16: 77–86. [DOI] [PubMed] [Google Scholar]
  • 53.Braidy N, Grant R, Brew BJ, Adams S, Jayasena T, Guillemin GJ. Effects of kynurenine pathway metabolites on intracellular NAD* synthesis. Int J Tryptophan Res 2009; 2: 61–69. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 54.Ting KK, Brew BJ, Guillemin GJ. Effect of quinolinic acid on human astrocytes morphology and functions: implications in Alzheimer's disease. J Neuroinflamm 2009; 6: 36. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 55.Guillemin GJ, Wang L, Brew BJ. Quinolinic acid selectively induces apoptosis of human astrocytes: potential role in AIDS dementia complex. J Neuroinflamm 2005; 2: 16. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 56.Potter MC, Elmer GI, Bergeron R, Albuqueque EX, Guidetti P, Wu HQ. Schwarcz R. Reduction of endogenous kymurenic acid formation enhances extracellular glutamate, hippocampal plasticity, and cognitive behavior. Neuropsychopharmacology 2010; 35: 1734–1742. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 57.Hansen LA, Masliah E, Galasko D, Terry RD. Plaque-only Alzheimer disease is usually the Lewy body variant, and vice versa. J Neuropathology Exp Neurol 1993; 52: 648–654. [DOI] [PubMed] [Google Scholar]

Articles from Redox Report : Communications in Free Radical Research are provided here courtesy of Taylor & Francis

RESOURCES