Journal of NeuroVirology

, Volume 8, Issue 6, pp 529–538 | Cite as

Local neuroinflammation and the progression of Alzheimer’s disease

  • Patrick L. McGeerEmail author
  • Edith G. McGeer


Postmortem immunohistochemical studies have revealed a state of chronic inflammation limited to lesioned areas of brain in Alzheimer’s disease. Some key actors in this inflammation are activated microglia (brain macrophages), proteins of the classical complement cascade, the pentraxins, cytokines, and chemokines. The inflammation does not involve the adaptive immune system or peripheral organs, but is rather due to the phylogenetically much older innate immune system, which appears to operate in most tissues of the body. Chronic inflammation can damage host tissue and the brain may be particularly vulnerable because of the postmitotic nature of neurons. Many of the inflammatory mediators have been shown to be locally produced and selectively elevated in affected regions of Alzheimer’s brain. Moreover, studies of tissue in such degenerative processes as atherosclerosis and infarcted heart suggest a similar local innate immune reaction may be important in such conditions. Much epidemiological and limited clinical evidence suggests that nonsteroidal anti-inflammatory drugs may impede the onset and slow the progression of Alzheimer’s disease. But these drugs strike at the periphery of the inflammatory reaction. Much better results might be obtained if drugs were found that could inhibit the activation of microglia or the complement system in brain, and combinations of drugs aimed at different inflammatory targets might be much more effective than single agents.


chemokines complement cytokines microglia NSAIDs pentraxins 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Aisen PS, Davis KL, et al (2000). A randomized controlled trial of prednisone in Alzheimer’s disease. Neurology 54: 588–593.PubMedGoogle Scholar
  2. Akiyama H, Yamada T, et al (1991). Association of amyloid P component with complement proteins in neurologically diseased tissue. Brain Res 548: 349–352.CrossRefPubMedGoogle Scholar
  3. Alldred A (2001). Etanercept in rheumatoid arthritis. Exp Opin Pharmacother 1: 1137–1148.CrossRefGoogle Scholar
  4. Asensio VC, Campbell IL (1999). Chemokines in the CNS: plurifunctional mediators in diverse states. Trends Neurosci 22: 504–512.CrossRefPubMedGoogle Scholar
  5. Bacon KB, Harrison JK (2000). Chemokines and their receptors in neurobiology: perspectives in physiology and homeostasis. J Neuroimmunol 104: 92–97.CrossRefPubMedGoogle Scholar
  6. Baik EJ, Kim EJ, et al (1999). Cyclooxygenase-2 selective inhibitors aggravate kainic acid induced seizure and neuronal cell death in the hippocampus. Brain Res 843: 118–129.CrossRefPubMedGoogle Scholar
  7. Blacker D, Wilcox MA, et al (1998). Alpha-2-macroglobulin is genetically associated with Alzheimer’s disease. Nat Genet 19: 357–360.CrossRefPubMedGoogle Scholar
  8. Broe GA, Grayson DA, et al (2000). Anti-inflammatory drugs protect against Alzheimer’s disease at low doses. Arch Neurol 57: 1586–1591.CrossRefPubMedGoogle Scholar
  9. Cacebelos R, Alvarez XA, et al (1994). Brain interleukin-1 beta in Alzheimer’s disease and vascular dementia. Methods Find Exp Clin Pharmacol 16: 141–145.Google Scholar
  10. Chapman GA, Moores K, et al (2000). Fractalkine cleavage from neuronal membranes represents an acute event in the inflammatory response to excitotoxic brain damage. J Neurosci 20: 2–6.Google Scholar
  11. Collin JS, Perry RT, et al (2000). Association of a haplo-type for tumor necrosis factor in siblings with late-onset Alzheimer’s disease: the NIMH Alzheimer’s disease genetics initiative. Am J Med Genet 96: 823–830.CrossRefGoogle Scholar
  12. Dickson DW, Lee SC, et al (1993). Microglia and cytokines in neurological disease, with special reference to AIDS and Alzheimer’s disease. Glia 7: 75–83.CrossRefPubMedGoogle Scholar
  13. Du Y, Dodel RC, et al (2000). Association of an interleukin 1 alpha polymorphism with Alzheimer’s disease. Neurology 55: 480–483.PubMedGoogle Scholar
  14. Eikelenboom P, Hack CE, et al (1989). Complement activation in amyloid plaques in Alzheimer’s dementia. Virchows Arch Cell Pathol 56: 259–262.CrossRefGoogle Scholar
  15. Ferreira SH, Moncada S, Vane JR (1973). Prostaglandins and the mechanism of analgesia produced by aspirin-like drugs. Brit J Pharmacol 49: 86–97.Google Scholar
  16. Fiane AE, Mollnes TE, et al (1999). Compstatin, a peptide inhibitor of C3, prolongs survival of exvivo perfused pig xenografts. Xenotransplantation 6: 52–65.CrossRefPubMedGoogle Scholar
  17. Furlong ST, Dutta AS, et al (2000). C3 activation is inhibited by analogs of compstatin but not by serine protease inhibitors or peptidyl alpha-ketoheterocycles. Immunopharmacology 48: 199–212.CrossRefPubMedGoogle Scholar
  18. Griffin WST, Stanley LC, et al (1989). Brain interleukin 1 and S-100 immunoreactivity are elevated in Down syndrome and Alzheimer’s disease. Proc Soc Natl Acad Sci USA 86: 7611–7615.CrossRefGoogle Scholar
  19. Grimaldi LM, Casadei VM, et al (2000). Association of early-onset Alzheimer’s disease with an interleukin-1α gene polymorphism. Ann Neurol 47: 361–365.CrossRefPubMedGoogle Scholar
  20. Hamilton K, Clair EW (2000). Tumour necrosis factor-alpha blockade: a new era for the effective management of rheumatoid arthritis. Exp Opin Pharmacother 1: 1041–1052.CrossRefGoogle Scholar
  21. Haymaker W, Adams RD (eds) (1982). Histology and histopathology of the nervous system. Charles C Thomas: Springfield, IL, pp 1150–1173.Google Scholar
  22. Hesselgesser J, Horuk R (1999). Chemokine and chemokine receptor expression in the central nervous system. J Neurovirol 5: 13–26.CrossRefPubMedGoogle Scholar
  23. Hicks PS, Saunero-Nazia L, et al (1992). Serum amyloid P component binds to histones and activates the classical complement pathway. J Immunol 149: 3689–3694.PubMedGoogle Scholar
  24. Hope HR, Remsen EE, et al (2000). Large-scale purification of myeloperoxidase from KL60 promyelocytic cells: characterization and comparison to human neutrophil myeloperoxidase. Protein Expr Purif 18: 269–276.CrossRefPubMedGoogle Scholar
  25. Ishii T, Haga S (1984). Immuno-electron-microscopic localization of complements in amyloid fibrils of senile plaques. Acta Neuropathol (Berlin) 63: 296–300.CrossRefGoogle Scholar
  26. Itagaki S, Akiyama H, et al (1994). Ultrastructural localization of complement membrane attack complex (MAC)-like immunoreactivity in brains of patients with Alzheimer’s disease. Brain Res 645: 78–84.CrossRefPubMedGoogle Scholar
  27. Jiang H, Robey F, et al (1992). Localization of sites through which C-reactive protein binds to and activates complement to residues 14–26 and 76–92 of the human C1q A chain. J Exp Med 175: 1373–1379.CrossRefPubMedGoogle Scholar
  28. Kamboh MI, Aston CE, et al (1997). Genetic effect of alpha-1-antichymotrypsin on the risk of Alzheimer’s disease. Genomics 40: 382–384.CrossRefPubMedGoogle Scholar
  29. Kaufmann WE, Worley PF, et al (1996). COX-2, a synaptically induced enzyme, is expressed by excitatory neurons at post-synaptic sites in rat cerebral cortex. Proc Natl Acad Sci USA 93: 2317–2321.CrossRefPubMedGoogle Scholar
  30. Klegeris A, McGeer PL (2000). Interaction of various intra-cellular signaling mechanisms involved in mononuclear phagocyte toxicity toward neuronal cells. J Leukoc Biol 67: 127–133.PubMedGoogle Scholar
  31. Klegeris A, Walker DG, et al (1999). Toxicity of human THP-1 monocytic cells towards neuron-like cells is reduced by non-steroidal anti-inflammatory drugs (NSAIDs). Neuropharmacology 38: 1017–1025.CrossRefPubMedGoogle Scholar
  32. Lagrand WK, Visser CA, et al (1999). C-reactive protein as a cardiovascular risk factor. Circulation 100: 96–102.PubMedGoogle Scholar
  33. Lambris DH (1993). The chemistry, biology, and phylogeny of C3. In: Complement today. Cruise JM, LLewis RE Jr (eds). Karger: Basel, pp 16–45.Google Scholar
  34. Licastro F, Pedrini S, et al (2000a). Polymorphisms of the IL-6 gene increase the risk for late onset Alzheimer’s disease and affect IL-6 plasma levels. Neurobiol Aging 21(1S): S38.CrossRefGoogle Scholar
  35. Licastro F, Pedrini S, et al (2000b). Gene polymorphism affecting α1-antichymotrypsin and interleukin-1 plasma levels increases Alzheimer’s disease risk. Ann Neurol 48: 388–391.CrossRefPubMedGoogle Scholar
  36. Lieberman AP, Pitha PM, et al (1989). Production of tumor necrosis factor and other cytokines by astrocytes stimulated with lipopolysaccharide or a neurotropic virus. Proc Natl Acad Sci USA 86: 6348–6352.CrossRefPubMedGoogle Scholar
  37. MacKenzie IRA (2000). Anti-inflammatory drugs and Alzheimer-type pathology in aging. Neurology 54: 732–734.PubMedGoogle Scholar
  38. McCusker SM (2001). Association between polymorphism in regulatory region of gene encoding tumour necrosis factor A and risk of Alzheimer’s disease and vascular dementia: a case-control study. Lancet 357: 436–439.CrossRefPubMedGoogle Scholar
  39. McGeer EG, Yasojima K, et al (2001). Inflammation in the pathogenesis of Parkinson’s disease. BC Med J 43: 138–141.Google Scholar
  40. McGeer PL (2000). Cyclooxygenase-2 inhibitors: rationale and therapeutic potential for Alzheimer’s disease. Drugs Aging 17: 1–11.CrossRefPubMedGoogle Scholar
  41. McGeer PL, Akiyama H, et al (1989). Immune system response in Alzheimer’s disease. Can J Neurol Sci 16: 516–527.PubMedGoogle Scholar
  42. McGeer PL, Harada N, et al (1992). Prevalence of dementia amongst elderly Japanese with leprosy: apparent effect of chronic drug therapy. Dementia 3: 146–149.Google Scholar
  43. McGeer PL, McGeer EG (1995). The inflammatory response system of brain: implications for therapy of Alzheimer’s and other neurodegenerative diseases. Brain Res Rev 21: 195–218.CrossRefPubMedGoogle Scholar
  44. McGeer PL, McGeer EG (2000). Autotoxicity and Alzheimer’s disease. Arch Neurol 57: 789–790.CrossRefPubMedGoogle Scholar
  45. McGeer PL, McGeer EG (2001). Polymorphisms in inflammatory genes enhance the risk of Alzheimer’s disease. Arch Neurol 58: 1790–1792.CrossRefPubMedGoogle Scholar
  46. McGeer PL, Rogers J, et al (1990). Anti-inflammatory drugs and Alzheimer’s disease? Lancet 335, 1037.CrossRefPubMedGoogle Scholar
  47. McGeer PL, Schulzer M, et al (1996). Arthritis and anti-inflammatory agents as possible protective factors for Alzheimer’s disease: a review of 17 epidemiological studies. Neurology 47: 425–432.PubMedGoogle Scholar
  48. Muir KW, Weir CJ, et al (1999). C-reactive protein and outcome after ischemic stroke. Stroke 30: 981–985.PubMedGoogle Scholar
  49. Nakayama M, Uchimura K, et al (1998). Cyclooxygenase-2 inhibition prevents delayed death of CA1 hippocampal neurons following global ischemia. Proc Natl Acad Sci USA 95: 10954–10959.CrossRefPubMedGoogle Scholar
  50. Neuroinflammation Working Group (2000). Inflammation and Alzheimer’s disease. Neurobiol Aging 21: 383–421.CrossRefGoogle Scholar
  51. Nicoll JAR, Mrak RE, et al (2000). Association of interleukin-1 gene polymorphisms with Alzheimer’s disease. Ann Neurol 47: 365–368.CrossRefPubMedGoogle Scholar
  52. Papassotiropoulos A, Bagli M, et al (1999). A genetic variation of the inflammatory cytokine interleukin-6 delays the initial onset and reduces the risk for sporadic Alzheimer’s disease. Ann Neurol 45: 666–668.CrossRefPubMedGoogle Scholar
  53. Pietila KO, Harmoinen AP, et al (1996). Serum C-reactive protein concentration in acute myocardial infarction and its relationship to mortality during 24 months of follow-up in patients under thrombolytic treatment. Eur Heart J 17: 1345–1349.PubMedGoogle Scholar
  54. Rebeck GW (2000). Confirmation of the genetic association of interleukin-1A with early onset sporadic Alzheimer’s disease. Neurosci Lett 293: 75–77.CrossRefPubMedGoogle Scholar
  55. Reynolds WF, Rhees J, et al (1999). Myeloperoxidase polymorphism is associated with gender specific risk for Alzheimer’s disease. Exp Neurol 155: 31–41.CrossRefPubMedGoogle Scholar
  56. Ridker PM, Hennekens CH, et al (2000). C-reactive protein and other markers of inflammation in the prediction of cardiovascular disease in women. N Engl J Med 342: 836–843.CrossRefPubMedGoogle Scholar
  57. Rogers J, Cooper NR, et al (1992). Complement activation by β-amyloid in Alzheimer’s disease. Proc Natl Acad Sci USA 89: 10016–10020.CrossRefPubMedGoogle Scholar
  58. Rogers J, Kirby LC, et al (1993). Clinical trial of indomethacin in Alzheimer’s disease. Neurology 43: 1609–1611.PubMedGoogle Scholar
  59. Sainati SM, Ingram DM, et al (2000). Results of a double-blind, placebo-controlled study of celecoxib for the progression of Alzheimer’s disease. In: Proceedings of 6th International Stockholm-Springfield Symposium of Advances in Alzheimer’s Therapy. p 180.Google Scholar
  60. Scharf S, Mander A, et al (1999). A double-blind, placebo-controlled trial of diclofenac misoprostol in Alzheimer’s disease. Neurology 53: 197–201.PubMedGoogle Scholar
  61. Schwartz CF, Kilgore KS, et al (1999). Increased rat cardiac allograft survival by the glycosaminoglycan pentosan polysulfate. J Surg Res 86: 24–28.CrossRefPubMedGoogle Scholar
  62. Sharif SF, Hariri RJ, et al (1993). Human astrocyte production of tumour necrosis factor-alpha, interleukin-1 beta, and interleukin-6 following exposure to lipopolysaccharide endotoxin. Neurol Res 15: 109–112.PubMedGoogle Scholar
  63. Stewart WF, Kawas C, et al (1997). Risk of Alzheimer’s disease and duration of NSAID use. Neurology 48: 626–632.PubMedGoogle Scholar
  64. Strittmatter WJ, Saunders A, et al (1993). Apolipoprotein E: high avidity binding to β-amyloid and increased frequency of type 4 allele in late-onset familial Alzheimer’s disease. Proc Natl Acad Sci USA 90: 1977–1981.CrossRefPubMedGoogle Scholar
  65. Tanhehco EJ, Kilgore KS, et al (1999). Reduction of myocardial infarct size after ischemia and reperfusion by the glycosaminoglycan pentosan polysulfate. J Cardiovasc Pharmacol 34: 153–161.CrossRefPubMedGoogle Scholar
  66. Van Gool WA, Weinstein HC, et al (2001). Effect of hydroxychloroquine on progression of dementia in early Alzheimer’s disease: an 18-month randomized, double-blind, placebo-controlled study. Lancet 358: 455–460.CrossRefPubMedGoogle Scholar
  67. Veld BAI, Ruitenberg A, et al (2000). Duration of non-steroidal antiinflammatory drug use and risk of Alzheimer’s disease. The Rotterdam study. Neurobiol Aging 21(1S): S204.CrossRefGoogle Scholar
  68. Veld BAI, Ruitenberg A, et al (2001). Nonsteroidal antiinflammatory drugs and the risk of Alzheimer’s disease. New Engl J Med 345: 1515–1521.CrossRefGoogle Scholar
  69. Walker DG, Kim SU, et al (1995). Complement and cytokine gene expression in cultured microglia derived from postmortem human brains. J Neurosci Res 40: 478–493.CrossRefPubMedGoogle Scholar
  70. Wallace JL, Pittman QJ, et al (1995). Nitric oxide-releasing NSAIDs: a novel class of GI-sparing anti-inflammatory drugs. Agents Actions 46(Suppl): 121–129.Google Scholar
  71. Webster S, Bonnell B, et al (1997a). Charge-based binding of complement component C1q to the Alzheimer’s amyloid beta-peptide. Am J Pathol 150: 1531–1536.PubMedGoogle Scholar
  72. Webster S, Lue LF, et al (1997b). Molecular and cellular characterization of the membrane attack complex, C5b-9, in Alzheimer’s disease. Neurobiol Aging 18: 415–421.CrossRefPubMedGoogle Scholar
  73. Wood JA, Wood PL, et al (1993). Cytokine indices in Alzheimer’s temporal cortex: no change in mature IL beta or IL-1RA but increases in the associated acute phase proteins IL-6, alpha 2-macroglobulin and C-reactive protein. Brain Res 629: 245–252.CrossRefPubMedGoogle Scholar
  74. Xia MQ, Qin SX, et al (1998). Immunohistochemical study of the beta-chemokine receptors CCR3 and CCR5 and their ligands in normal and Alzheimer’s disease brains. Am J Pathol 153: 31–37.PubMedGoogle Scholar
  75. Yamabe T, Dhir G, et al (1994). Cytokine-gene expression in measles-infected adult human glial cells. J Neuroimmunol 49: 171–179.CrossRefPubMedGoogle Scholar
  76. Yasojima K, McGeer EG, et al (1999a). Complement regulators C1 inhibitor and CD59 do not significantly inhibit complement activation in Alzheimer’s disease. Brain Res 833: 297–301.CrossRefPubMedGoogle Scholar
  77. Yasojima K, Schwab C, et al (1998). Human heart generates complement proteins that are upregulated and activated after myocardial infarction. Circ Res 83: 860–869.PubMedGoogle Scholar
  78. Yasojima K, Schwab C, et al (1999b). Upregulated production and activation of the complement system in Alzheimer’s disease brain. Am J Pathol 154: 927–936.PubMedGoogle Scholar
  79. Yasojima K, Schwab C, et al (1999c). Distribution of cyclooxygenase-1 and cyclooxygenase-2 mRNAs and proteins in human brain and peripheral organs. Brain Res 830: 226–236.CrossRefPubMedGoogle Scholar
  80. Yasojima K, Schwab C, et al (2000). Human neurons generate C-reactive protein and amyloid P: upregulation in Alzheimer’s disease. Brain Res 887: 80–89.CrossRefPubMedGoogle Scholar
  81. Yasojima K, Schwab C, et al (2001). Generation of C-reactive protein and complement components in atherosclerotic plaques. Am J Pathol 158: 1039–1051.PubMedGoogle Scholar
  82. Ying SC, Gewurz AT, et al (1993). Human serum amyloid P component oligomers bind and activate the classical complement pathway via residues 14–26 and 76–92 of the A chain collagen-like region of C1q. J Immunol 150: 169–176.PubMedGoogle Scholar
  83. Zlotnik A, Yoshie O (2000). Chemokines: a new classification system and their role in immunity. Immunity 12: 121–127.CrossRefPubMedGoogle Scholar
  84. Zujovic V, Benavides J, et al (2000). Fractalkine modulates TNF-alpha secretion and neurotoxicity induced by microglial activator. Glia 29: 305–315.CrossRefPubMedGoogle Scholar

Copyright information

© Journal of NeuroVirology, Inc. 2002

Authors and Affiliations

  1. 1.Kinsmen Laboratory of Neurological Research, Department of PsychiatryUniversity of British ColumbiaVancouverCanada

Personalised recommendations