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Increased quinolinic acid in peripheral mononuclear cells in Alzheimer’s dementia

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European Archives of Psychiatry and Clinical Neuroscience Aims and scope Submit manuscript

Abstract

The role of monocytes and macrophages in the pathogenesis of neurodegenerative disorders such as Alzheimer’s disease (AD) is poorly understood. Recently, we have shown that the number of CD14+ monocytes remained constant during healthy aging and in AD patients. Although only little is known about the function of activated macrophages and microglia in AD, one important mechanism involves the expression of quinolinic acid (QUIN), an endogenous N-methyl-d-aspartate glutamate receptor (NMDA-R) agonist which mediates excitotoxicity especially in the hippocampus. We used immunofluorescence stainings of PBMCs to determine the expression of quinolinic acid (QUIN) and the MHC class II molecule HLA-DR in peripheral monocytic cells in 51 healthy volunteers aged 22–87 years and 43 patients with AD at diagnosis (0 weeks) and during the course of rivastigmine treatment at 0.25 year (12 weeks), 0.5 year (30 weeks), 1 year, and 1.5 years. The number of QUIN+ HLA-DR+ cells rises in healthy persons aged 30–40 years compared to persons aged 60–70 years, indicating that this cell population increases with aging. AD patients at diagnosis had an increased frequency of QUIN+, QUIN+ HLA-DR+, and QUIN+ HLA-DR+/HLA-DR+ cells compared to aged-matched controls. These cell populations remained increased in AD for up to one year after initiation of treatment with rivastigmine; no alterations were detected in aged healthy persons. We conclude that the expression of the neurotoxic agent QUIN is increased in peripheral monocytes from AD patients. These cells could enter the brain and contribute to excitotoxicity.

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References

  1. Akiyama H, Barger S, Barnum S, Bradt B, Bauer J, Cole GM, Cooper NR, Eikelenboom P, Emmerling M, Fiebich BL, Finch CE, Frautschy S, Griffin WS, Hampel H, Hull M, Landreth G, Lue L, Mrak R, Mackenzie IR, McGeer PL, O’Banion MK, Pachter J, Pasinetti G, Plata-Salaman C, Rogers J, Rydel R, Shen Y, Streit W, Strohmeyer R, Tooyoma I, Van Muiswinkel FL, Veerhuis R, Walker D, Webster S, Wegrzyniak B, Wenk G, Wyss-Coray T (2000) Inflammation and Alzheimer’s disease. Neurobiol Aging 21:383–421

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  2. Bate C, Kempster S, Last V, Williams A (2006) Interferon-gamma increases neuronal death in response to amyloid-beta1-42. J Neuroinflam 3:7

    Article  CAS  Google Scholar 

  3. Belkhelfa M, Rafa H, Medjeber O, Arroul-Lammali A, Behairi N, Abada-Bendib M, Makrelouf M, Belarbi S, Masmoudi AN, Tazir M, Touil-Boukoffa C (2014) IFN-gamma and TNF-alpha are involved during Alzheimer disease progression and correlate with nitric oxide production: a study in Algerian patients. J Interferon Cytokine Res 34:839–847

    Article  PubMed  CAS  Google Scholar 

  4. Braidy N, Guillemin GJ, Mansour H, Chan-Ling T, Grant R (2011) Changes in kynurenine pathway metabolism in the brain, liver and kidney of aged female Wistar rats. FEBS J 278:4425–4434

    Article  PubMed  CAS  Google Scholar 

  5. Browne TC, McQuillan K, McManus RM, O’Reilly JA, Mills KH, Lynch MA (2013) IFN-gamma Production by amyloid beta-specific Th1 cells promotes microglial activation and increases plaque burden in a mouse model of Alzheimer’s disease. J Immunol 190:2241–2251

    Article  PubMed  CAS  Google Scholar 

  6. Busse S, Brix B, Kunschmann R, Bogerts B, Stoecker W, Busse M (2014) N-methyl-d-aspartate glutamate receptor (NMDA-R) antibodies in mild cognitive impairment and dementias. Neurosci Res 85:58–64

    Article  PubMed  CAS  Google Scholar 

  7. Busse S, Busse M, Brix B, Probst C, Genz A, Bogerts B, Stoecker W, Steiner J (2014) Seroprevalence of N-methyl-d-aspartate glutamate receptor (NMDA-R) autoantibodies in aging subjects without neuropsychiatric disorders and in dementia patients. Eur Arch Psychiatry Clin Neurosci 264:545–550

    Article  PubMed  Google Scholar 

  8. Busse S, Steiner J, Alter J, Dobrowolny H, Mawrin C, Bogerts B, Hartig R, Busse M (2015) Expression of HLA-DR, CD80, and CD86 in healthy aging and Alzheimer’s disease. J Alzheimers Dis 47:177–184

    Article  PubMed  CAS  Google Scholar 

  9. Busse S, Steiner J, Glorius S, Dobrowolny H, Greiner-Bohl S, Mawrin C, Bommhardt U, Hartig R, Bogerts B, Busse M (2015) VGF expression by T lymphocytes in patients with Alzheimer’s disease. Oncotarget (in press)

  10. Casal JA, Robles A, Tutor JC (2003) Serum markers of monocyte/macrophage activation in patients with Alzheimer’s disease and other types of dementia. Clin Biochem 36:553–556

    Article  PubMed  CAS  Google Scholar 

  11. Chiarugi A, Calvani M, Meli E, Traggiai E, Moroni F (2001) Synthesis and release of neurotoxic kynurenine metabolites by human monocyte-derived macrophages. J Neuroimmunol 120:190–198

    Article  PubMed  CAS  Google Scholar 

  12. Fiala M, Liu QN, Sayre J, Pop V, Brahmandam V, Graves MC, Vinters HV (2002) Cyclooxygenase-2-positive macrophages infiltrate the Alzheimer’s disease brain and damage the blood-brain barrier. Eur J Clin Invest 32:360–371

    Article  PubMed  CAS  Google Scholar 

  13. Fietta A, Merlini C, De Bernardi PM, Gandola L, Piccioni PD, Grassi C (1993) Non specific immunity in aged healthy subjects and in patients with chronic bronchitis. 5:357–361

  14. Franceschi C, Bonafe M, Valensin S (2000) Human immunosenescence: the prevailing of innate immunity, the failing of clonotypic immunity, and the filling of immunological space. Vaccine 18:1717–1720

    Article  PubMed  CAS  Google Scholar 

  15. Giacobini E (2001) Is anti-cholinesterase therapy of Alzheimer’s disease delaying progression? 13:247–254

  16. Giavarotti L, Simon KA, Azzalis LA, Fonseca FL, Lima AF, Freitas MC, Brunialti MK, Salomao R, Moscardi AA, Montano MB, Ramos LR, Junqueira VB (2013) Mild systemic oxidative stress in the subclinical stage of Alzheimer’s disease. Oxidat Med Cell Long 2013:609019

    Google Scholar 

  17. Guillemin GJ, Croitoru-Lamoury J, Dormont D, Armati PJ, Brew BJ (2003) Quinolinic acid upregulates chemokine production and chemokine receptor expression in astrocytes. Glia 41:371–381

    Article  PubMed  Google Scholar 

  18. Guillemin GJ, Smith DG, Smythe GA, Armati PJ, Brew BJ (2003) Expression of the kynurenine pathway enzymes in human microglia and macrophages. Adv Exp Med Biol 527:105–112

    Article  PubMed  CAS  Google Scholar 

  19. Guillemin GJ, Smythe G, Takikawa O, Brew BJ (2005) Expression of indoleamine 2,3-dioxygenase and production of quinolinic acid by human microglia, astrocytes, and neurons. Glia 49:15–23

    Article  PubMed  Google Scholar 

  20. Guillemin GJ, Smythe GA, Veas LA, Takikawa O, Brew BJ (2003) A beta 1–42 induces production of quinolinic acid by human macrophages and microglia. Neuroreport 14:2311–2315

    Article  PubMed  CAS  Google Scholar 

  21. Guillemin GJ, Williams KR, Smith DG, Smythe GA, Croitoru-Lamoury J, Brew BJ (2003) Quinolinic acid in the pathogenesis of Alzheimer’s disease. Adv Exp Med Biol 527:167–176

    Article  PubMed  CAS  Google Scholar 

  22. Kaduszkiewicz H, Zimmermann T, Beck-Bornholdt HP, van den Bussche H (2005) Cholinesterase inhibitors for patients with Alzheimer’s disease: systematic review of randomised clinical trials. BMJ (Clin Res Ed) 331:321–327

  23. Kusdra L, Rempel H, Yaffe K, Pulliam L (2000) Elevation of CD69 + monocyte/macrophages in patients with Alzheimer’s disease. Immunobiology 202:26–33

    Article  PubMed  CAS  Google Scholar 

  24. Lloberas J, Celada A (2002) Effect of aging on macrophage function. Exp Gerontol 37:1325–1331

    Article  PubMed  CAS  Google Scholar 

  25. Maes M, Mihaylova I, Ruyter MD, Kubera M, Bosmans E (2007) The immune effects of TRYCATs (tryptophan catabolites along the IDO pathway): relevance for depression - and other conditions characterized by tryptophan depletion induced by inflammation. Neuro Endocrinol Lett 28:826–831

    PubMed  CAS  Google Scholar 

  26. Milstien S, Sakai N, Brew BJ, Krieger C, Vickers JH, Saito K, Heyes MP (1994) Cerebrospinal fluid nitrite/nitrate levels in neurologic diseases. J Neurochem 63:1178–1180

    Article  PubMed  CAS  Google Scholar 

  27. Mourdian MM, Heyes MP, Pan JB, Heuser IJ, Markey SP, Chase TN, Mouradian MM (1989) No changes in central quinolinic acid levels in Alzheimer’s disease. Neurosci Lett 105:233–238

    Article  PubMed  CAS  Google Scholar 

  28. Pemberton LA, Kerr SJ, Smythe G, Brew BJ (1997) Quinolinic acid production by macrophages stimulated with IFN-gamma, TNF-alpha, and IFN-alpha. J Interferon Cytokine Res 17:589–595

    Article  PubMed  CAS  Google Scholar 

  29. Plowden J, Renshaw-Hoelscher M, Engleman C, Katz J, Sambhara S (2004) Innate immunity in aging: impact on macrophage function. Aging Cell 3:161–167

    Article  PubMed  CAS  Google Scholar 

  30. Rahman A, Ting K, Cullen KM, Braidy N, Brew BJ, Guillemin GJ (2009) The excitotoxin quinolinic acid induces tau phosphorylation in human neurons. PloS One 4:e6344

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  31. Raine CS (2000) Inflammation in Alzheimer’s disease: a view from the periphery. Neurobiol Aging 21:437–440 (discussion 451–433)

    Article  PubMed  CAS  Google Scholar 

  32. Reale M, Iarlori C, Gambi F, Feliciani C, Salone A, Toma L, DeLuca G, Salvatore M, Conti P, Gambi D (2004) Treatment with an acetylcholinesterase inhibitor in Alzheimer patients modulates the expression and production of the pro-inflammatory and anti-inflammatory cytokines. J Neuroimmunol 148:162–171

    Article  PubMed  CAS  Google Scholar 

  33. Reitz C, Mayeux R (2014) Alzheimer disease: epidemiology, diagnostic criteria, risk factors and biomarkers. Biochem Pharmacol 88:640–651

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  34. Rogers J, Luber-Narod J, Styren SD, Civin WH (1988) Expression of immune system-associated antigens by cells of the human central nervous system: relationship to the pathology of Alzheimer’s disease. Neurobiol Aging 9:339–349

    Article  PubMed  CAS  Google Scholar 

  35. Schwarcz R, Kohler C (1983) Differential vulnerability of central neurons of the rat to quinolinic acid. Neurosci Lett 38:85–90

    Article  PubMed  CAS  Google Scholar 

  36. Selley ML, Close DR, Stern SE (2002) The effect of increased concentrations of homocysteine on the concentration of (E)-4-hydroxy-2-nonenal in the plasma and cerebrospinal fluid of patients with Alzheimer’s disease. Neurobiol Aging 23:383–388

    Article  PubMed  CAS  Google Scholar 

  37. Serpente M, Bonsi R, Scarpini E, Galimberti D (2014) Innate immune system and inflammation in Alzheimer’s disease: from pathogenesis to treatment. Neuroimmunomodulation 21:79–87

    Article  PubMed  CAS  Google Scholar 

  38. Stone TW, Behan WM (2007) Interleukin-1beta but not tumor necrosis factor-alpha potentiates neuronal damage by quinolinic acid: protection by an adenosine A2A receptor antagonist. J Neurosci Res 85:1077–1085

    Article  PubMed  CAS  Google Scholar 

  39. Swardfager W, Lanctot K, Rothenburg L, Wong A, Cappell J, Herrmann N (2010) A meta-analysis of cytokines in Alzheimer’s disease. Biol Psychiatry 68:930–941

    Article  PubMed  CAS  Google Scholar 

  40. Wada H (1998) Blood-brain barrier permeability of the demented elderly as studied by cerebrospinal fluid-serum albumin ratio. Intern Med (Tokyo, Japan) 37:509–513

  41. Widner B, Leblhuber F, Walli J, Tilz GP, Demel U, Fuchs D (2000) Tryptophan degradation and immune activation in Alzheimer’s disease. J Neural Transm (Vienna) 107:343–353

    Article  PubMed  CAS  Google Scholar 

  42. Winblad B, Engedal K, Soininen H, Verhey F, Waldemar G, Wimo A, Wetterholm AL, Zhang R, Haglund A, Subbiah P (2001) A 1-year, randomized, placebo-controlled study of donepezil in patients with mild to moderate AD. Neurology 57:489–495

    Article  PubMed  CAS  Google Scholar 

  43. Yamada A, Akimoto H, Kagawa S, Guillemin GJ, Takikawa O (2009) Proinflammatory cytokine interferon-gamma increases induction of indoleamine 2,3-dioxygenase in monocytic cells primed with amyloid beta peptide 1–42: implications for the pathogenesis of Alzheimer’s disease. J Neurochem 110:791–800

    Article  PubMed  CAS  Google Scholar 

  44. Yamamoto M, Kiyota T, Horiba M, Buescher JL, Walsh SM, Gendelman HE, Ikezu T (2007) Interferon-gamma and tumor necrosis factor-alpha regulate amyloid-beta plaque deposition and beta-secretase expression in Swedish mutant APP transgenic mice. Am J Pathol 170:680–692

    Article  PubMed  PubMed Central  CAS  Google Scholar 

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Acknowledgements

We are grateful to Bianca Jerzykiewicz for her skilful medical technical assistance. We thank Novartis for financial support of our research.

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Correspondence to Mandy Busse.

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Busse, M., Hettler, V., Fischer, V. et al. Increased quinolinic acid in peripheral mononuclear cells in Alzheimer’s dementia. Eur Arch Psychiatry Clin Neurosci 268, 493–500 (2018). https://doi.org/10.1007/s00406-017-0785-y

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  • DOI: https://doi.org/10.1007/s00406-017-0785-y

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