Neurochemical Research

, Volume 32, Issue 10, pp 1749–1756 | Cite as

Inflammation, Depression and Dementia: Are they Connected?

Original Paper

Abstract

Chronic inflammation is now considered to be central to the pathogenesis not only of such medical disorders as cardiovascular disease, multiple sclerosis, diabetes and cancer but also of major depression. If chronic inflammatory changes are a common feature of depression, this could predispose depressed patients to neurodegenerative changes in later life. Indeed there is now clinical evidence that depression is a common antecedent of Alzheimer’s disease and may be an early manifestation of dementia before the cognitive declines becomes apparent. This review summarises the evidence that links chronic low grade inflammation with changes in brain structure that could precipitate neurodegenerative changes associated with Alzheimer’s disease and other dementias. For example, neuronal loss is a common feature of major depression and dementia. It is hypothesised that the progress from depression to dementia could result from the activation of macrophages in the blood, and microglia in the brain, that release pro-inflammatory cytokines. Such cytokines stimulate a cascade of inflammatory changes (such as an increase in prostaglandin E2, nitric oxide in addition to more pro-inflammatory cytokines) and a hypersecretion of cortisol. The latter steroid inhibits protein synthesis thereby reducing the synthesis of neurotrophic factors and preventing reairto damages neuronal networks. In addition, neurotoxic end products of the tryptophan-kynurenine pathway, such as quinolinic acid, accumulate in astrocytes and neurons in both depression and dementia. Thus increased neurodegeneration, reduced neuroprotection and neuronal repair are common pathological features of major depression and dementia. Such changes may help to explain why major depression is a frequent prelude to dementia in later life.

Keywords

Pro-inflammatory cytokines Cortisol Tryptophan-kynurenine pathway Macrophages Microglia Neurotoxicity 

References

  1. 1.
    Leonard BE (1989) The amine hypothesis of depression: a reassessment. In: TiptonK F, Youdim MBH (eds) Biochemical and pharmacological aspects of depression. Taylor and Francis, London, pp 25–49Google Scholar
  2. 2.
    Brambilla F (2000) Psychoneuroendocriniligy: research on the pituitary-adrenal-cortical system. Psychosomat Med 62:576–607Google Scholar
  3. 3.
    Jonas BS, Laudo JF (2000) Negative affect as a prospective risk factor of hypertension. Psychosomat Med 62:188–196Google Scholar
  4. 4.
    Leonard BE (2006) Physical consequences of depression. Quart J mental Health 1:33–38Google Scholar
  5. 5.
    Herbert TB, Cohen S (1993) Depression and immunity: a meta-analytic view. Psychol Bull 113:472–486PubMedCrossRefGoogle Scholar
  6. 6.
    Maes M (1999) Major depression and activation of the inflammatory response. Adv Exp Biol Med 461:25–46CrossRefGoogle Scholar
  7. 7.
    Evans DL (2005) Mood disorders in the medically ill: scientific review and recommendations. Biol Psychiat 58:175–189PubMedCrossRefGoogle Scholar
  8. 8.
    Geerlings MI, Schoevers RA, Beckman AT et al (2000) Depression and risk of cognitive decline and Alzheimer’s disease. Results of 2 prospective community based studies in the Netherlands. Br J Psychiat 176:568–575CrossRefGoogle Scholar
  9. 9.
    Steffens DC, Plassman BL, Helms MJ et al (1997) A twin study of late onset depression and apolipoprotein E4 as risk factors for Alzheimer’s disease. Biol Psychiat 41:851–856PubMedCrossRefGoogle Scholar
  10. 10.
    Song C, Dinan TG, Leonard BE (1994) Changes in immunoglobulins, complement and acute phase proteins in depressed patients and normal controls. J Affect Dis 30:283–288PubMedCrossRefGoogle Scholar
  11. 11.
    Ford DE, Erlinger TP (2004) Depression and C-reactive protein in U.S. adults. Arch Intern Med 164:1010–1014PubMedCrossRefGoogle Scholar
  12. 12.
    Lanquillon S (2000) Cytokine production and treatment response in major depressive disorder. Neuropsychopharmacology 22:370–379PubMedCrossRefGoogle Scholar
  13. 13.
    Levine J (2000) Cerebrospinal cytokine levels in patients with acute depression. Neuropsychobiology 40:171–176CrossRefGoogle Scholar
  14. 14.
    Yu YW (2003) Association study of the IL-1 beta (C-511T) genetic polymorphism with major depressive disorder, associated symptomatology and antidepressant response. Neuropsychopharmacology 28:1182–1185PubMedGoogle Scholar
  15. 15.
    Jun TY (2003) Possible association between -G308A TNF alpha gene polymorphism and major depressive disorder in a Korean population. Psychiat Genet 13:179–181CrossRefGoogle Scholar
  16. 16.
    Suarez EC (2004) Enhanced expression of cytokines and chemokines by blood monocytes to in vitro lipopolysaccharide stimulation is associated with hostility and severity of depressive symptoms in healthy women. Psychoneuroendocrinology 29:1119–1128PubMedCrossRefGoogle Scholar
  17. 17.
    van der Ven A (2003) Herpes viruses,cytokines and altered haemostsis in vital exhaustion. Psychosomat Med 65:194–200CrossRefGoogle Scholar
  18. 18.
    Leonard BE, Song C (2007) Stress, the immune system and depression. In: Encyclopedia of stress. Elsevier North Holland Press. (in press)Google Scholar
  19. 19.
    Haack M (1999) Plasma levels of cytokines and soluble cytokine receptors in psychiatric patients upon hospital admission: effects of confounding factors and depression. J Pdsychiat Res 33:407–418CrossRefGoogle Scholar
  20. 20.
    Steptoe A (2003) Lack of association between depressive symptoms and markers of immune and vascular inflammation in middle aged men and women. Psychol Med 33:667–674PubMedCrossRefGoogle Scholar
  21. 21.
    Miller GE (2003) Pathways linking depression, adiposity and inflammatory markers in healthy young adults. Brain Behav Immun 17:276–285PubMedCrossRefGoogle Scholar
  22. 22.
    Owen BM (2001) Raised levels of plasma IL-1 beta in major and post viral depression. Acta Psychiat Scand 103:226–228PubMedCrossRefGoogle Scholar
  23. 23.
    Tiermeier H (2003) Inflammatory proteins and depression in the elderly. Epidemiology 14:103–107CrossRefGoogle Scholar
  24. 24.
    Sluzewska A, Rybakowski J, Bosmans E. et al (1996) Indicators of immune activation in major depression. Psychiat Res 64:162–167CrossRefGoogle Scholar
  25. 25.
    Myint A-M, Leonard BE, Steinbusch HW, Kim Y-K (2005) Thi, Th2 and Th3 cytokine alteratikons in major depression. J Affect Dis 88:169–173Google Scholar
  26. 26.
    Smith R (1991) The macrophage theory of depression. Med Hypoth 35:298–306CrossRefGoogle Scholar
  27. 27.
    Wichers MC,Koek GH,Robaeys G et al (2005) IDO and interferon alpha induced`depressive symptoms: a shift in hypothesis from tryptophan depletion. Mol Psychiat 10:538–544CrossRefGoogle Scholar
  28. 28.
    Meyers CA, Valentine AD (1995) Neurologic and psychiatric adverse effects of immunological therapy. CNS Drugs 3:56–68CrossRefGoogle Scholar
  29. 29.
    Minden SL, Schiffer RB (1990) Affective disorder in multiple sclerosis. Gen Hosp Psychiatry 9:426–434CrossRefGoogle Scholar
  30. 30.
    Marshall PS (1993) Allergy and depression: a neurochemical threshold model of the relation between the illnesses. Psychol Bull 113:23–43PubMedCrossRefGoogle Scholar
  31. 31.
    Katon W, Sullivan MD (1990) Depression and chronic medical illness. J Clin Psychiatry 51:3–11PubMedGoogle Scholar
  32. 32.
    Schrott LM, Crnic LS (1996) Anxiety behavior, exploratory behavior and activitZBx and NZB F1 hybrid mice: role of genotype and autoimmune disease progression. Brain Behav Immun 10:260–274PubMedCrossRefGoogle Scholar
  33. 33.
    Myint A-M, Kim Y-K (2003) Cytokine-serotonin interactions through indoleamine 2,3-dioxygenase: a neurodegenerative hypothesis of depression. Med Hypoth 61:519–525CrossRefGoogle Scholar
  34. 34.
    Capuron L (2002) Association between decreased serum tryptophan concentrations and depressive symptoms in cancer patients undergoin cytokine therapy. Mol Psychiat 7:468–473CrossRefGoogle Scholar
  35. 35.
    Capuron L (2003) Association of exaggerated HPA axis response to the initial injection of IFN alpha with development of depression during IFN alpha therapy. Am J Psychiat 160:1342–1345PubMedCrossRefGoogle Scholar
  36. 36.
    Juenling FD (2000) Prefrontal cortical hypometabolism during low dose IFN alpha treatment. Psychopharmacology 152:383–389CrossRefGoogle Scholar
  37. 37.
    Capuron L (2005) Anterior cingulate activation and error processing during IFN alpha treatment. Biol Psychiatry 58:190–196PubMedCrossRefGoogle Scholar
  38. 38.
    Cummings JL (2004) Alzheimer’s disease. N Engl J Med 351:565–567CrossRefGoogle Scholar
  39. 39.
    Selkoe DJ (2004) Alzheimer’s disease: mechanistic understanding predictors novel therapies. Ann Intern Med 140:627–638PubMedGoogle Scholar
  40. 40.
    Mattson MP (2004) Pathways towards and away from Alzheimer’s disease. Nature 430:631–639PubMedCrossRefGoogle Scholar
  41. 41.
    Hewett SJ, Csernansky CA, Choi DW (1994) Selective potentiation of NMDA induced neural injury following induction of astrocytic iNOS. Neuron 13:487–494PubMedCrossRefGoogle Scholar
  42. 42.
    Song C, Horrobin DF, Leonard BE (2006) The comparison of changes in behaviour, neurochemistry, endocrine and immune functions after different routes, doses and durations of administration of IL-1 beta in rats. Pharmacopsychiatry 39:88–99PubMedCrossRefGoogle Scholar
  43. 43.
    Herx LM, Rivest S, Young VW (2000) CNS initiated inflammation and neurotrophism in trauma: IL-1 beta is required for the production of ciliary neurotrophic factor. J Immunol 165:2232–2239PubMedGoogle Scholar
  44. 44.
    Strjbos P, Rothwell N (1995) IL-1 beta attenuates excitatory amino acid neurodegeneration in vitro: involement of NGF. J Neurosci 15:3468–3474Google Scholar
  45. 45.
    Vandenabecle P, Fiers W (1991) Is amyloidogenesis during Alzheimer’s disease due to an IL-1/IL-6 mediated acute phase reaction in the brain? Immunol Today 12:217–219CrossRefGoogle Scholar
  46. 46.
    Grimaldi LM, Casadrei VM, Ferri C et al (2000) Association of early onset Alzheimer’s disease with IL-1 alpha gene polymorphism. Ann Neurol 47:361–365PubMedCrossRefGoogle Scholar
  47. 47.
    Meda L, Cassatella MA, Szendrei GI et al (1995) Activation of microglial cells bt beta amyloid protein and IFN gamma. Nature 374:647–650PubMedCrossRefGoogle Scholar
  48. 48.
    Sciacca FL, Ferri C, Licastro F et al (2003) IL-1beta polymorphism is associated with age at onset of Alzheimer’s disease. Neurobiol Aging 24:927–931PubMedCrossRefGoogle Scholar
  49. 49.
    Norris JG, Benveniste EN (1993) IL-6 production by astrocytes: induction by norepinephrine. J Neuroimmunol 45:137–145PubMedCrossRefGoogle Scholar
  50. 50.
    Ye SM, Johnson RW (1999) Increased IL-6 expression by microglia from brain of aged mice. J Neuroimmunol 93:139–148PubMedCrossRefGoogle Scholar
  51. 51.
    Gradient RA, Otten V (1993) Differential expression of IL-6 and IL-6 receptor on RNA’s in rat hypothalamus. Neurosci Lett 153:13–16CrossRefGoogle Scholar
  52. 52.
    Qui Z, Sweeney DD, Netzeband JG, Grud DL (1998) Chronic IL-6 alters NMDA receptor mediated membrane responses and enhances neurotoxicity in developing CNS neurons. J Neurosci 18:10445–10456Google Scholar
  53. 53.
    Tarkowski E, Blennow K, Wallin A, Tarkowski A (1999) Intracerebral production of TNF alpha, a local neuroprotective agent, in Alzheimer’s disease and vascular dementia. J Clin Immunol 19:223–230PubMedCrossRefGoogle Scholar
  54. 54.
    Lanzem AS, Johnston CM, Perry VH et al (1998) Longitudinal study of inflammatory factors in serum, CSF and brain tissue in Alzheimer’s disease: IL-1 beta, IL-6,IL-1 receptor antagonist, TNF alpha, soluble TNF receptors and alpha-chymotrypsin. Alzheim Dis Assoc Disord 12:215–227CrossRefGoogle Scholar
  55. 55.
    Knezevic-Cuca J, Stansberry KB, Johnston G et al (2000) Neurotrophic role of IL-6 and soluble IL-6 receptor in NIE-115 neuroblastoma cells. J Neuroimmunol 102:8–16PubMedCrossRefGoogle Scholar
  56. 56.
    Blasko I, Marx F, Steiner E et al (1999) TNF alpha plus IFN gamma induce production oif Alzheimer beta amyloid peptides and decrease secretion of amyloid precursor proteins. FASEB J 13:63–68PubMedGoogle Scholar
  57. 57.
    McCusker SM, Curran MD, Dynan KB et al (2001) Association between polymorphism in regulating region of gene encoding TNF alpha and risk of Alzheimer’s disease and vascular dementia: a case controlled study. Lancet 357:436–439PubMedCrossRefGoogle Scholar
  58. 58.
    Infante J, Llorca J, Berciano J, Combarros O (2002) No synergistic effect between 850 TNF alpha promoter polymorphism and APOE epsilon 4 allele in Alzheimer’s disease. Neurosci Lett 328:71–73PubMedCrossRefGoogle Scholar
  59. 59.
    Mitrasinovic OM, Perez GV, Zhao F et al (2001) Overexpression of macrophage colony stimulating factor receptor on microglial cells induces an inflammatory response. J biol Chem 276:30142–30149PubMedCrossRefGoogle Scholar
  60. 60.
    Finch CE, Laping NJ, Morgan TE et al (1993) TGF beta 1 is an organiser of responses to neurodegeneration. J cell Biochem 53:314–322PubMedCrossRefGoogle Scholar
  61. 61.
    Flanders KC, Ren RF, Lippa VCF (1998) TGF betas in neurodegenerative disease. Prog Neurobiol Biol Psychiatry 54:71–85CrossRefGoogle Scholar
  62. 62.
    Kanne SM, Balota DA, Storandt M et al (1998) Relating anatomy to function in Alzheimer’s disease: neuropsychological profiles predict regional neuropathology 5 years later. Neurol 50:979–985Google Scholar
  63. 63.
    Lyketos CG, Olin J (2002) Depression in Alzheimer’s disease: overview and treatment. Biol Psychiatry 52:243–252CrossRefGoogle Scholar
  64. 64.
    Rapp MA, Dahlman K, Sano M et al (2005) Neuropsychological differences between late onset and recurrent geriatric major depression. Am J Psychiatry 162:691–698PubMedCrossRefGoogle Scholar
  65. 65.
    Guillemin GJ, Kerr SJ, Smythe GA et al (2001) The kynurenine pathway metabolism in human astrocytes: pathway for neuroprotection. J Neurochem 78:842–853PubMedCrossRefGoogle Scholar
  66. 66.
    Hayaishi O Biochemical and medical aspects of tryptophan metabolism Elsevier: Amsterdam/North Holland Biomed (Press)Google Scholar
  67. 67.
    Kim JP, Choi DW (1987) Quinolinate neurotoxicity in cortical cell cultures. Neurosci 23:423–432CrossRefGoogle Scholar
  68. 68.
    Stone TW, Darlington LG (2002) Endogenous kynurenines as targets for drug discovery and development. Nat Rev Drug Discov 1:609–620PubMedCrossRefGoogle Scholar
  69. 69.
    Heyes MP, Achim CL, Wiley CA et al (1996) Human microglia convert l-tryptophan into neurotoxic quiolinic acid. Biochem J 320(pt.2):595–597PubMedGoogle Scholar
  70. 70.
    Butterfield DA, Casegna A, Lauderback CM, Drake J (2002) Evidence that amyloid beta peptide induced lipid peroxidation and its sequelae in Alzheimer’s brain contribute to neural death. Neurobiol Aging 23:655–664PubMedCrossRefGoogle Scholar
  71. 71.
    Heyes MP, Saito K, Major EO et al (1993) A mechanism of quinolinic acid formation by brain in inflammatory neurological disease. Brain 16:1425–1450Google Scholar
  72. 72.
    Markesberry WR (1997) Oxidative stress hypothesis in Alzheimer’s disease. Free Radic Biol Med 23:134–147CrossRefGoogle Scholar
  73. 73.
    Hartai Z, Juhasz A, Rimanoczy A et al Decreased serum and red blood cell kynurenic acid levels in Alzheimer’s disease.Neurochem.Int.doi:10.1016/j.neuint.2006.08.012Google Scholar
  74. 74.
    Leonard BE, Myint A-M (2006) Inflammation and depression: is there a causal connection with dementia? Neurotox Res 10:149–160PubMedCrossRefGoogle Scholar
  75. 75.
    Vythingham M (2002) Childhood trauma associated with smaller hippocampal volume in women with major depression. Am J Psychiat 159:2072–2080CrossRefGoogle Scholar
  76. 76.
    Malberg JE, Eisch AJ, Nessler EJ, Duman RS (2000) Chronic antidepressant treatment imcreases neurogenesis in adult rat hippocampus. J Neurosci 20:9104–9110PubMedGoogle Scholar
  77. 77.
    Santarelli L (2003) Requirement of hippocampal neurogenesis for the behavioural effects of antidepressants. Science 301:805–809PubMedCrossRefGoogle Scholar
  78. 78.
    Saivanen M, Lucas G, Emfors P et al (2005) BDNF and antidepressants have different but co-ordinated effects on neural turnoiver, proliferation and survival in the adult dendate gyrus. J Neurosci 25:1089–1094CrossRefGoogle Scholar
  79. 79.
    Nibuya M, Takahashi M, Russell DS, Duman RS (1999) Chronic stress increases catalytic TrkB mRNA in rat hippocampus. Neurosci Lett 267:81–84PubMedCrossRefGoogle Scholar
  80. 80.
    Vaidya VA, Siuciak JA, Du F, Duman RS (1999) Hippocampal mossy fibre sprouting induced by chronic ECS. Neurosci 898:157–166CrossRefGoogle Scholar
  81. 81.
    Fujioka T, Fujioka A, Duman RS (2004) Activation of cAMP signalling facilitates the morphological maturation of new born neurons in adult hippocampus. J Neurosci 24:319–328PubMedCrossRefGoogle Scholar
  82. 82.
    Song H, Poo M (2001) The cell biology of neuronal navigation. Nat Cell Biol 3:E81–E88PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2007

Authors and Affiliations

  1. 1.Department of Psychiatry and Neuropsychology, Brain and Behaviour Research InstituteUniversity of MaastrichtMaastrichtThe Netherlands
  2. 2.Pharmacology DepartmentNational University of IrelandGalwayIreland

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