Skip to main content

Advertisement

Log in

Inflammatory Cytokines and Alzheimer’s Disease: A Review from the Perspective of Genetic Polymorphisms

  • Review
  • Published:
Neuroscience Bulletin Aims and scope Submit manuscript

Abstract

Neuroinflammatory processes are a central feature of Alzheimer’s disease (AD) in which microglia are over-activated, resulting in the increased production of pro-inflammatory cytokines. Moreover, deficiencies in the anti-inflammatory system may also contribute to neuroinflammation. Recently, advanced methods for the analysis of genetic polymorphisms have further supported the relationship between neuroinflammatory factors and AD risk because a series of polymorphisms in inflammation-related genes have been shown to be associated with AD. In this review, we summarize the polymorphisms of both pro- and anti-inflammatory cytokines related to AD, primarily interleukin-1 (IL-1), IL-6, tumor necrosis factor alpha, IL-4, IL-10, and transforming growth factor beta, as well as their functional activity in AD pathology. Exploration of the relationship between inflammatory cytokine polymorphisms and AD risk may facilitate our understanding of AD pathogenesis and contribute to improved treatment strategies.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1

Similar content being viewed by others

References

  1. Golde TE, Petrucelli L, Lewis J. Targeting Abeta and tau in Alzheimer’s disease, an early interim report. Exp Neurol 2010, 223: 252–266.

    Article  CAS  PubMed  Google Scholar 

  2. Bonda DJ, Wang X, Lee HG, Smith MA, Perry G, Zhu X. Neuronal failure in Alzheimer’s disease: a view through the oxidative stress looking-glass. Neurosci Bull 2014, 30: 243–252.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Dorey E, Chang N, Liu QY, Yang Z, Zhang W. Apolipoprotein E, amyloid-beta, and neuroinflammation in Alzheimer’s disease. Neurosci Bull 2014, 30: 317–330.

    Article  CAS  PubMed  Google Scholar 

  4. Cagnin A, Brooks DJ, Kennedy AM, Gunn RN, Myers R, Turkheimer FE, et al. In-vivo measurement of activated microglia in dementia. Lancet 2001, 358: 461–467.

    Article  CAS  PubMed  Google Scholar 

  5. Yasojima K, Schwab C, McGeer EG, McGeer PL. Up-regulated production and activation of the complement system in Alzheimer’s disease brain. Am J Pathol 1999, 154: 927–936.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  7. Sui X, Liu J, Yang X. Cerebrospinal fluid biomarkers of Alzheimer’s disease. Neurosci Bull 2014, 30: 233–242.

    Article  CAS  PubMed  Google Scholar 

  8. Vlad SC, Miller DR, Kowall NW, Felson DT. Protective effects of NSAIDs on the development of Alzheimer disease. Neurology 2008, 70: 1672–1677.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Karch CM, Goate AM. Alzheimer’s disease risk genes and mechanisms of disease pathogenesis. Biol Psychiatry 2015, 77: 43–51.

    Article  CAS  PubMed  Google Scholar 

  10. Zhang DF, Li J, Wu H, Cui Y, Bi R, Zhou HJ, et al. CFH Variants affect structural and functional brain changes and genetic risk of Alzheimer’s disease. Neuropsychopharmacology 2016, 41: 1034–1045.

    Article  CAS  PubMed  Google Scholar 

  11. Wang HZ, Bi R, Hu QX, Xiang Q, Zhang C, Zhang DF, et al. Validating GWAS-identified risk Loci for Alzheimer’s disease in Han Chinese populations. Mol Neurobiol 2016, 53: 379–390.

    Article  CAS  PubMed  Google Scholar 

  12. Li Y, Song D, Jiang Y, Wang J, Feng R, Zhang L, et al. CR1 rs3818361 polymorphism contributes to Alzheimer’s disease susceptibility in Chinese population. Mol Neurobiol 2016, 53: 4054–4059.

  13. Li X, Shen N, Zhang S, Liu J, Jiang Q, Liao M, et al. CD33 rs3865444 polymorphism contributes to Alzheimer’s disease susceptibility in Chinese, European, and North American populations. Mol Neurobiol 2015, 52: 414–421.

    Article  CAS  PubMed  Google Scholar 

  14. Qin X, Peng Q, Zeng Z, Chen Z, Lin L, Deng Y, et al. Interleukin-1A -889C/T polymorphism and risk of Alzheimer’s disease: a meta-analysis based on 32 case-control studies. J Neurol 2012, 259: 1519–1529.

    Article  CAS  PubMed  Google Scholar 

  15. Hua Y, Zhao H, Kong Y, Lu X. Meta-analysis of the association between the interleukin-1A -889C/T polymorphism and Alzheimer’s disease. J Neurosci Res 2012, 90: 1681–1692.

    Article  CAS  PubMed  Google Scholar 

  16. Hayes A, Green EK, Pritchard A, Harris JM, Zhang Y, Lambert JC, et al. A polymorphic variation in the interleukin 1A gene increases brain microglial cell activity in Alzheimer’s disease. J Neurol Neurosurg Psychiatry 2004, 75: 1475–1477.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Yuan H, Xia Q, Ge P, Wu S. Genetic polymorphism of interleukin 1beta -511C/T and susceptibility to sporadic Alzheimer’s disease: a meta-analysis. Mol Biol Rep 2013, 40: 1827–1834.

    Article  CAS  PubMed  Google Scholar 

  18. Di Bona D, Plaia A, Vasto S, Cavallone L, Lescai F, Franceschi C, et al. Association between the interleukin-1beta polymorphisms and Alzheimer’s disease: a systematic review and meta-analysis. Brain Res Rev 2008, 59: 155–163.

    Article  PubMed  CAS  Google Scholar 

  19. Ehl C, Kolsch H, Ptok U, Jessen F, Schmitz S, Frahnert C, et al. Association of an interleukin-1beta gene polymorphism at position -511 with Alzheimer’s disease. Int J Mol Med 2003, 11: 235–238.

    CAS  PubMed  Google Scholar 

  20. Ravaglia G, Paola F, Maioli F, Martelli M, Montesi F, Bastagli L, et al. Interleukin-1beta and interleukin-6 gene polymorphisms as risk factors for AD: a prospective study. Exp Gerontol 2006, 41: 85–92.

    Article  CAS  PubMed  Google Scholar 

  21. Sciacca FL, Ferri C, Licastro F, Veglia F, Biunno I, Gavazzi A, et al. Interleukin-1B polymorphism is associated with age at onset of Alzheimer’s disease. Neurobiol Aging 2003, 24: 927–931.

    Article  CAS  PubMed  Google Scholar 

  22. Licastro F, Veglia F, Chiappelli M, Grimaldi LM, Masliah E. A polymorphism of the interleukin-1 beta gene at position +3953 influences progression and neuro-pathological hallmarks of Alzheimer’s disease. Neurobiol Aging 2004, 25: 1017–1022.

    Article  CAS  PubMed  Google Scholar 

  23. Flex A, Giovannini S, Biscetti F, Liperoti R, Spalletta G, Straface G, et al. Effect of proinflammatory gene polymorphisms on the risk of Alzheimer’s disease. Neurodegener Dis 2014, 13: 230–236.

    CAS  PubMed  Google Scholar 

  24. Qi HP, Qu ZY, Duan SR, Wei SQ, Wen SR, Bi S. IL-6-174 G/C and -572 C/G polymorphisms and risk of Alzheimer’s disease. PLoS One 2012, 7: e37858.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Hua Y, Guo X, Huang Q, Kong Y, Lu X. Association between interleukin-6 -174G/C polymorphism and the risk of Alzheimer’s disease: a meta-analysis. Int J Neurosci 2013, 123: 626–635.

    Article  CAS  PubMed  Google Scholar 

  26. Licastro F, Grimaldi LM, Bonafe M, Martina C, Olivieri F, Cavallone L, et al. Interleukin-6 gene alleles affect the risk of Alzheimer’s disease and levels of the cytokine in blood and brain. Neurobiol Aging 2003, 24: 921–926.

    Article  CAS  PubMed  Google Scholar 

  27. Wang M, Jia J. The interleukin-6 gene -572C/G promoter polymorphism modifies Alzheimer’s risk in APOE epsilon 4 carriers. Neurosci Lett 2010, 482: 260–263.

    Article  CAS  PubMed  Google Scholar 

  28. He MX, Yang WL, Zhang MM, Lian YJ, Hua HY, Zeng JS, et al. Association between interleukin-6 gene promoter -572C/G polymorphism and the risk of sporadic Alzheimer’s disease. Neurol Sci 2010, 31: 165–168.

    Article  PubMed  Google Scholar 

  29. Di Bona D, Candore G, Franceschi C, Licastro F, Colonna-Romano G, Camma C, et al. Systematic review by meta-analyses on the possible role of TNF-alpha polymorphisms in association with Alzheimer’s disease. Brain Res Rev 2009, 61: 60–68.

    Article  PubMed  CAS  Google Scholar 

  30. Lee YH, Choi SJ, Ji JD, Song GG. Association between TNF-alpha promoter -308 A/G polymorphism and Alzheimer’s disease: a meta-analysis. Neurol Sci 2015, 36: 825–832.

    Article  PubMed  Google Scholar 

  31. Lio D, Annoni G, Licastro F, Crivello A, Forte GI, Scola L, et al. Tumor necrosis factor-alpha -308A/G polymorphism is associated with age at onset of Alzheimer’s disease. Mech Ageing Dev 2006, 127: 567–571.

    Article  CAS  PubMed  Google Scholar 

  32. Liu SY, Zeng FF, Chen ZW, Wang CY, Zhao B, Li KS. Vascular endothelial growth factor gene promoter polymorphisms and Alzheimer’s disease risk: a meta-analysis. CNS Neurosci Ther 2013, 19: 469–476.

    Article  CAS  PubMed  Google Scholar 

  33. Bossu P, Ciaramella A, Moro ML, Bellincampi L, Bernardini S, Federici G, et al. Interleukin 18 gene polymorphisms predict risk and outcome of Alzheimer’s disease. J Neurol Neurosurg Psychiatry 2007, 78: 807–811.

    Article  PubMed  PubMed Central  Google Scholar 

  34. Yu JT, Tan L, Song JH, Sun YP, Chen W, Miao D, et al. Interleukin-18 promoter polymorphisms and risk of late onset Alzheimer’s disease. Brain Res 2009, 1253: 169–175.

    Article  CAS  PubMed  Google Scholar 

  35. Bossu P, Ciaramella A, Salani F, Bizzoni F, Varsi E, Di Iulio F, et al. Interleukin-18 produced by peripheral blood cells is increased in Alzheimer’s disease and correlates with cognitive impairment. Brain Behav Immun 2008, 22: 487–492.

    Article  CAS  PubMed  Google Scholar 

  36. Chapuis J, Hot D, Hansmannel F, Kerdraon O, Ferreira S, Hubans C, et al. Transcriptomic and genetic studies identify IL-33 as a candidate gene for Alzheimer’s disease. Mol Psychiatry 2009, 14: 1004–1016.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Zhu XC, Tan L, Jiang T, Tan MS, Zhang W, Yu JT. Association of IL-12A and IL-12B polymorphisms with Alzheimer’s disease susceptibility in a Han Chinese population. J Neuroimmunol 2014, 274: 180–184.

    Article  CAS  PubMed  Google Scholar 

  38. Ribizzi G, Fiordoro S, Barocci S, Ferrari E, Megna M. Cytokine polymorphisms and Alzheimer disease: possible associations. Neurol Sci 2010, 31: 321–325.

    Article  CAS  PubMed  Google Scholar 

  39. Li W, Qian X, Teng H, Ding Y, Zhang L. Association of interleukin-4 genetic polymorphisms with sporadic Alzheimer’s disease in Chinese Han population. Neurosci Lett 2014, 563: 17–21.

    Article  CAS  PubMed  Google Scholar 

  40. Zhang Y, Zhang J, Tian C, Xiao Y, Li X, He C, et al. The -1082G/A polymorphism in IL-10 gene is associated with risk of Alzheimer’s disease: a meta-analysis. J Neurol Sci 2011, 303: 133–138.

    Article  CAS  PubMed  Google Scholar 

  41. Di Bona D, Rizzo C, Bonaventura G, Candore G, Caruso C. Association between interleukin-10 polymorphisms and Alzheimer’s disease: a systematic review and meta-analysis. J Alzheimers Dis 2012, 29: 751–759.

    PubMed  Google Scholar 

  42. Moraes CF, Benedet AL, Souza VC, Lins TC, Camargos EF, Naves JO, et al. Cytokine gene polymorphisms and Alzheimer’s disease in Brazil. Neuroimmunomodulation 2013, 20: 239–246.

    Article  CAS  PubMed  Google Scholar 

  43. Arosio B, Bergamaschini L, Galimberti L, La Porta C, Zanetti M, Calabresi C, et al. +10 T/C polymorphisms in the gene of transforming growth factor-beta1 are associated with neurodegeneration and its clinical evolution. Mech Ageing Dev 2007, 128: 553–557.

    Article  CAS  PubMed  Google Scholar 

  44. Caraci F, Bosco P, Signorelli M, Spada RS, Cosentino FI, Toscano G, et al. The CC genotype of transforming growth factor-beta1 increases the risk of late-onset Alzheimer’s disease and is associated with AD-related depression. Eur Neuropsychopharmacol 2012, 22: 281–289.

    Article  CAS  PubMed  Google Scholar 

  45. Hamaguchi T, Okino S, Sodeyama N, Itoh Y, Takahashi A, Otomo E, et al. Association of a polymorphism of the transforming growth factor-beta1 gene with cerebral amyloid angiopathy. J Neurol Neurosurg Psychiatry 2005, 76: 696–699.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Peila R, Yucesoy B, White LR, Johnson V, Kashon ML, Wu K, et al. A TGF-beta1 polymorphism association with dementia and neuropathologies: the HAAS. Neurobiol Aging 2007, 28: 1367–1373.

    Article  CAS  PubMed  Google Scholar 

  47. Luedecking EK, DeKosky ST, Mehdi H, Ganguli M, Kamboh MI. Analysis of genetic polymorphisms in the transforming growth factor-beta1 gene and the risk of Alzheimer’s disease. Hum Genet 2000, 106: 565–569.

    Article  CAS  PubMed  Google Scholar 

  48. Griffin WS, Stanley LC, Ling C, White L, MacLeod V, Perrot LJ, et al. Brain interleukin 1 and S-100 immunoreactivity are elevated in Down syndrome and Alzheimer disease. Proc Natl Acad Sci USA 1989, 86: 7611–7615.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Li Y, Liu L, Kang J, Sheng JG, Barger SW, Mrak RE, et al. Neuronal-glial interactions mediated by interleukin-1 enhance neuronal acetylcholinesterase activity and mRNA expression. J Neurosci 2000, 20: 149–155.

    PubMed  Google Scholar 

  50. Griffin WS, Mrak RE. Interleukin-1 in the genesis and progression of and risk for development of neuronal degeneration in Alzheimer’s disease. J Leukoc Biol 2002, 72: 233–238.

    CAS  PubMed  PubMed Central  Google Scholar 

  51. Sheng JG, Jones RA, Zhou XQ, McGinness JM, Van Eldik LJ, Mrak RE, et al. Interleukin-1 promotion of MAPK-p38 overexpression in experimental animals and in Alzheimer’s disease: potential significance for tau protein phosphorylation. Neurochem Int 2001, 39: 341–348.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Combarros O, Sanchez-Guerra M, Infante J, Llorca J, Berciano J. Gene dose-dependent association of interleukin-1A [-889] allele 2 polymorphism with Alzheimer’s disease. J Neurol 2002, 249: 1242–1245.

    Article  CAS  PubMed  Google Scholar 

  53. Combarros O, Llorca J, Sanchez-Guerra M, Infante J, Berciano J. Age-dependent association between interleukin-1A (-889) genetic polymorphism and sporadic Alzheimer’s disease. A meta-analysis. J Neurol 2003, 250: 987–989.

    CAS  PubMed  Google Scholar 

  54. Yildiz SH, Erdogan MO, Artan S, Solak M, Yaman M, Ozbabalik BD, et al. Association of Alzheimer’s disease with APOE and IL-1alpha gene polymorphisms. Am J Alzheimers Dis Other Demen 2015, 30: 756–761.

    Article  PubMed  Google Scholar 

  55. Serretti A, Olgiati P, Politis A, Malitas P, Albani D, Dusi S, et al. Lack of association between interleukin-1 alpha rs1800587 polymorphism and Alzheimer’s disease in two Independent European samples. J Alzheimers Dis 2009, 16: 181–187.

    CAS  PubMed  Google Scholar 

  56. Wei X, Chen X, Fontanilla C, Zhao L, Liang Z, Dodel R, et al. C/T conversion alters interleukin-1A promoter function in a human astrocyte cell line. Life Sci 2007, 80: 1152–1156.

    Article  CAS  PubMed  Google Scholar 

  57. Dominici R, Cattaneo M, Malferrari G, Archi D, Mariani C, Grimaldi LM, et al. Cloning and functional analysis of the allelic polymorphism in the transcription regulatory region of interleukin-1 alpha. Immunogenetics 2002, 54: 82–86.

    Article  CAS  PubMed  Google Scholar 

  58. Murphy GM, Jr., Claassen JD, DeVoss JJ, Pascoe N, Taylor J, Tinklenberg JR, et al. Rate of cognitive decline in AD is accelerated by the interleukin-1 alpha -889 *1 allele. Neurology 2001, 56: 1595–1597.

    Article  CAS  PubMed  Google Scholar 

  59. Yucesoy B, Peila R, White LR, Wu KM, Johnson VJ, Kashon ML, et al. Association of interleukin-1 gene polymorphisms with dementia in a community-based sample: the Honolulu-Asia Aging Study. Neurobiol Aging 2006, 27: 211–217.

    Article  CAS  PubMed  Google Scholar 

  60. Hedley R, Hallmayer J, Groth DM, Brooks WS, Gandy SE, Martins RN. Association of interleukin-1 polymorphisms with Alzheimer’s disease in Australia. Ann Neurol 2002, 51: 795–797.

    Article  CAS  PubMed  Google Scholar 

  61. Dundar NO, Aktekin B, Ekinci NC, Sahinturk D, Yavuzer U, Yegin O, et al. Interleukin-1beta secretion in hippocampal sclerosis patients with mesial temporal lobe epilepsy. Neurol Int 2013, 5: e17.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  62. Santtila S, Savinainen K, Hurme M. Presence of the IL-1RA allele 2 (IL1RN*2) is associated with enhanced IL-1beta production in vitro. Scand J Immunol 1998, 47: 195–198.

    Article  CAS  PubMed  Google Scholar 

  63. Payao SL, Goncalves GM, de Labio RW, Horiguchi L, Mizumoto I, Rasmussen LT, et al. Association of interleukin 1beta polymorphisms and haplotypes with Alzheimer’s disease. J Neuroimmunol 2012, 247: 59–62.

    Article  CAS  PubMed  Google Scholar 

  64. Ma SL, Tang NL, Lam LC, Chiu HF. Lack of association of the interleukin-1beta gene polymorphism with Alzheimer’s disease in a Chinese population. Dement Geriatr Cogn Disord 2003, 16: 265–268.

    Article  CAS  PubMed  Google Scholar 

  65. Eriksson UK, Pedersen NL, Reynolds CA, Hong MG, Prince JA, Gatz M, et al. Associations of gene sequence variation and serum levels of C-reactive protein and interleukin-6 with Alzheimer’s disease and dementia. J Alzheimers Dis 2011, 23: 361–369.

    CAS  PubMed  PubMed Central  Google Scholar 

  66. Strauss S, Bauer J, Ganter U, Jonas U, Berger M, Volk B. Detection of interleukin-6 and alpha 2-macroglobulin immunoreactivity in cortex and hippocampus of Alzheimer’s disease patients. Lab Invest 1992, 66: 223–230.

    CAS  PubMed  Google Scholar 

  67. Quintanilla RA, Orellana DI, Gonzalez-Billault C, Maccioni RB. Interleukin-6 induces Alzheimer-type phosphorylation of tau protein by deregulating the cdk5/p35 pathway. Exp Cell Res 2004, 295: 245–257.

    Article  CAS  PubMed  Google Scholar 

  68. Pola R, Flex A, Gaetani E, Lago AD, Gerardino L, Pola P, et al. The -174 G/C polymorphism of the interleukin-6 gene promoter is associated with Alzheimer’s disease in an Italian population [corrected]. Neuroreport 2002, 13: 1645–1647.

    Article  CAS  PubMed  Google Scholar 

  69. Fontalba A, Gutierrez O, Llorca J, Mateo I, Vazquez-Higuera JL, Berciano J, et al. Gene-gene interaction between CARD8 and interleukin-6 reduces Alzheimer’s disease risk. J Neurol 2009, 256: 1184–1186.

    Article  PubMed  Google Scholar 

  70. Capurso C, Solfrizzi V, Colacicco AM, D’Introno A, Frisardi V, Imbimbo BP, et al. Interleukin 6-174 G/C promoter and variable number of tandem repeats (VNTR) gene polymorphisms in sporadic Alzheimer’s disease. Prog Neuropsychopharmacol Biol Psychiatry 2010, 34: 177–182.

    Article  CAS  PubMed  Google Scholar 

  71. Han XM, Wang CH, Sima X, Liu SY. Interleukin-6 -174G/C polymorphism and the risk of Alzheimer’s disease in Caucasians: a meta-analysis. Neurosci Lett 2011, 504: 4–8.

    Article  CAS  PubMed  Google Scholar 

  72. Fishman D, Faulds G, Jeffery R, Mohamed-Ali V, Yudkin JS, Humphries S, et al. The effect of novel polymorphisms in the interleukin-6 (IL-6) gene on IL-6 transcription and plasma IL-6 levels, and an association with systemic-onset juvenile chronic arthritis. J Clin Invest 1998, 102: 1369–1376.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. van Oijen M, Arp PP, de Jong FJ, Hofman A, Koudstaal PJ, Uitterlinden AG, et al. Polymorphisms in the interleukin 6 and transforming growth factor beta1 gene and risk of dementia. The Rotterdam Study. Neurosci Lett 2006, 402: 113–117.

    Article  PubMed  CAS  Google Scholar 

  74. Deming Y, Xia J, Cai Y, Lord J, Holmans P, Bertelsen S, et al. A potential endophenotype for Alzheimer’s disease: cerebrospinal fluid clusterin. Neurobiol Aging 2016, 37: 208 e201–e209.

    Google Scholar 

  75. Nishimura M, Sakamoto T, Kaji R, Kawakami H. Influence of polymorphisms in the genes for cytokines and glutathione S-transferase omega on sporadic Alzheimer’s disease. Neurosci Lett 2004, 368: 140–143.

    Article  CAS  PubMed  Google Scholar 

  76. Rasmussen L, Delabio R, Horiguchi L, Mizumoto I, Terazaki CR, Mazzotti D, et al. Association between interleukin 6 gene haplotype and Alzheimer’s disease: a Brazilian case-control study. J Alzheimers Dis 2013, 36: 733–738.

    CAS  PubMed  Google Scholar 

  77. Janelsins MC, Mastrangelo MA, Park KM, Sudol KL, Narrow WC, Oddo S, et al. Chronic neuron-specific tumor necrosis factor-alpha expression enhances the local inflammatory environment ultimately leading to neuronal death in 3xTg-AD mice. Am J Pathol 2008, 173: 1768–1782.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Tobinick E, Gross H, Weinberger A, Cohen H. TNF-alpha modulation for treatment of Alzheimer’s disease: a 6-month pilot study. MedGenMed 2006, 8: 25.

    PubMed  PubMed Central  Google Scholar 

  79. McAlpine FE, Lee JK, Harms AS, Ruhn KA, Blurton-Jones M, Hong J, et al. Inhibition of soluble TNF signaling in a mouse model of Alzheimer’s disease prevents pre-plaque amyloid-associated neuropathology. Neurobiol Dis 2009, 34: 163–177.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Montgomery SL, Mastrangelo MA, Habib D, Narrow WC, Knowlden SA, Wright TW, et al. Ablation of TNF-RI/RII expression in Alzheimer’s disease mice leads to an unexpected enhancement of pathology: implications for chronic pan-TNF-alpha suppressive therapeutic strategies in the brain. Am J Pathol 2011, 179: 2053–2070.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Cheng X, Yang L, He P, Li R, Shen Y. Differential activation of tumor necrosis factor receptors distinguishes between brains from Alzheimer’s disease and non-demented patients. J Alzheimers Dis 2010, 19: 621–630.

    CAS  PubMed  PubMed Central  Google Scholar 

  82. He P, Zhong Z, Lindholm K, Berning L, Lee W, Lemere C, et al. Deletion of tumor necrosis factor death receptor inhibits amyloid beta generation and prevents learning and memory deficits in Alzheimer’s mice. J Cell Biol 2007, 178: 829–841.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Li R, Yang L, Lindholm K, Konishi Y, Yue X, Hampel H, et al. Tumor necrosis factor death receptor signaling cascade is required for amyloid-beta protein-induced neuron death. J Neurosci 2004, 24: 1760–1771.

    Article  CAS  PubMed  Google Scholar 

  84. Montgomery SL, Narrow WC, Mastrangelo MA, Olschowka JA, O’Banion MK, Bowers WJ. Chronic neuron- and age-selective down-regulation of TNF receptor expression in triple-transgenic Alzheimer disease mice leads to significant modulation of amyloid- and Tau-related pathologies. Am J Pathol 2013, 182: 2285–2297.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Manoochehri M, Kamali K, Rahgozar M, Ohadi M, Farrokhi H, Khorshid HR. Lack of association between tumor necrosis factor-alpha -308 G/A polymorphism and risk of developing late-onset Alzheimer’s disease in an Iranian population. Avicenna J Med Biotechnol 2009, 1: 193–197.

    CAS  PubMed  PubMed Central  Google Scholar 

  86. Vural P, Degirmencioglu S, Parildar-Karpuzoglu H, Dogru-Abbasoglu S, Hanagasi HA, Karadag B, et al. The combinations of TNFalpha-308 and IL-6 -174 or IL-10 -1082 genes polymorphisms suggest an association with susceptibility to sporadic late-onset Alzheimer’s disease. Acta Neurol Scand 2009, 120: 396–401.

    Article  CAS  PubMed  Google Scholar 

  87. Maggioli E, Boiocchi C, Zorzetto M, Sinforiani E, Cereda C, Ricevuti G, et al. The human leukocyte antigen class III haplotype approach: new insight in Alzheimer’s disease inflammation hypothesis. Curr Alzheimer Res 2013, 10: 1047–1056.

    Article  CAS  PubMed  Google Scholar 

  88. Ardebili SM, Yeghaneh T, Gharesouran J, Rezazadeh M, Farhoudi M, Ayromlou H, et al. Genetic association of TNF-alpha-308 G/A and -863 C/A polymorphisms with late onset Alzheimer’s disease in Azeri Turk population of Iran. J Res Med Sci 2011, 16: 1006–1013.

    CAS  PubMed  PubMed Central  Google Scholar 

  89. Sarajarvi T, Helisalmi S, Antikainen L, Makinen P, Koivisto AM, Herukka SK, et al. An association study of 21 potential Alzheimer’s disease risk genes in a Finnish population. J Alzheimers Dis 2010, 21: 763–767.

    PubMed  Google Scholar 

  90. Wilson AG, Symons JA, McDowell TL, McDevitt HO, Duff GW. Effects of a polymorphism in the human tumor necrosis factor alpha promoter on transcriptional activation. Proc Natl Acad Sci USA 1997, 94: 3195–3199.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Lau S, Bates KA, Sohrabi HR, Rodrigues M, Martins G, Dhaliwal SS, et al. Functional effects of genetic polymorphism in inflammatory genes in subjective memory complainers. Neurobiol Aging 2012, 33: 1054–1056.

    Article  CAS  PubMed  Google Scholar 

  92. Tang H, Mao X, Xie L, Greenberg DA, Jin K. Expression level of vascular endothelial growth factor in hippocampus is associated with cognitive impairment in patients with Alzheimer’s disease. Neurobiol Aging 2013, 34: 1412–1415.

    Article  PubMed  CAS  Google Scholar 

  93. Kalaria RN, Cohen DL, Premkumar DR, Nag S, LaManna JC, Lust WD. Vascular endothelial growth factor in Alzheimer’s disease and experimental cerebral ischemia. Brain Res Mol Brain Res 1998, 62: 101–105.

    Article  CAS  PubMed  Google Scholar 

  94. Sanchez A, Tripathy D, Luo J, Yin X, Martinez J, Grammas P. Neurovascular unit and the effects of dosage in VEGF toxicity: role for oxidative stress and thrombin. J Alzheimers Dis 2013, 34: 281–291.

    CAS  PubMed  Google Scholar 

  95. Del Bo R, Ghezzi S, Scarpini E, Bresolin N, Comi GP. VEGF genetic variability is associated with increased risk of developing Alzheimer’s disease. J Neurol Sci 2009, 283: 66–68.

    Article  PubMed  CAS  Google Scholar 

  96. He D, Lu W, Chang K, Liu Y, Zhang J, Zeng Z. Vascular endothelial growth factor polymorphisms and risk of Alzheimer’s disease: a meta-analysis. Gene 2013, 518: 296–302.

    Article  CAS  PubMed  Google Scholar 

  97. Shahbazi M, Fryer AA, Pravica V, Brogan IJ, Ramsay HM, Hutchinson IV, et al. Vascular endothelial growth factor gene polymorphisms are associated with acute renal allograft rejection. J Am Soc Nephrol 2002, 13: 260–264.

    CAS  PubMed  Google Scholar 

  98. Cao L, Jiao X, Zuzga DS, Liu Y, Fong DM, Young D, et al. VEGF links hippocampal activity with neurogenesis, learning and memory. Nat Genet 2004, 36: 827–835.

    Article  CAS  PubMed  Google Scholar 

  99. Felderhoff-Mueser U, Schmidt OI, Oberholzer A, Buhrer C, Stahel PF. IL-18: a key player in neuroinflammation and neurodegeneration? Trends Neurosci 2005, 28: 487–493.

    Article  CAS  PubMed  Google Scholar 

  100. Ojala J, Alafuzoff I, Herukka SK, van Groen T, Tanila H, Pirttila T. Expression of interleukin-18 is increased in the brains of Alzheimer’s disease patients. Neurobiol Aging 2009, 30: 198–209.

    Article  CAS  PubMed  Google Scholar 

  101. Segat L, Milanese M, Arosio B, Vergani C, Crovella S. Lack of association between Interleukin-18 gene promoter polymorphisms and onset of Alzheimer’s disease. Neurobiol Aging 2010, 31: 162–164.

    Article  CAS  PubMed  Google Scholar 

  102. Yu JT, Song JH, Wang ND, Wu ZC, Zhang Q, Zhang N, et al. Implication of IL-33 gene polymorphism in Chinese patients with Alzheimer’s disease. Neurobiol Aging 2012, 33: 1014 e1011–e1014.

    Google Scholar 

  103. Vom Berg J, Prokop S, Miller KR, Obst J, Kalin RE, Lopategui-Cabezas I, et al. Inhibition of IL-12/IL-23 signaling reduces Alzheimer’s disease-like pathology and cognitive decline. Nat Med 2012, 18: 1812–1819.

  104. Tan MS, Yu JT, Jiang T, Zhu XC, Guan HS, Tan L. IL12/23 p40 inhibition ameliorates Alzheimer’s disease-associated neuropathology and spatial memory in SAMP8 mice. J Alzheimers Dis 2014, 38: 633–646.

    CAS  PubMed  Google Scholar 

  105. Liu L, Xu Y, Liu Z, Chen J, Zhang Y, Zhu J, et al. IL12 polymorphisms, HBV infection and risk of hepatocellular carcinoma in a high-risk Chinese population. Int J Cancer 2011, 128: 1692–1696.

    Article  CAS  PubMed  Google Scholar 

  106. Stanilova S, Miteva L. Taq-I polymorphism in 3’UTR of the IL-12B and association with IL-12p40 production from human PBMC. Genes Immun 2005, 6: 364–366.

    Article  CAS  PubMed  Google Scholar 

  107. Reale M, Iarlori C, Feliciani C, Gambi D. Peripheral chemokine receptors, their ligands, cytokines and Alzheimer’s disease. J Alzheimers Dis 2008, 14: 147–159.

    CAS  PubMed  Google Scholar 

  108. Shimizu E, Kawahara K, Kajizono M, Sawada M, Nakayama H. IL-4-induced selective clearance of oligomeric beta-amyloid peptide(1-42) by rat primary type 2 microglia. J Immunol 2008, 181: 6503–6513.

    Article  CAS  PubMed  Google Scholar 

  109. Kawahara K, Suenobu M, Yoshida A, Koga K, Hyodo A, Ohtsuka H, et al. Intracerebral microinjection of interleukin-4/interleukin-13 reduces beta-amyloid accumulation in the ipsilateral side and improves cognitive deficits in young amyloid precursor protein 23 mice. Neuroscience 2012, 207: 243–260.

    Article  CAS  PubMed  Google Scholar 

  110. Arai N, Nomura D, Villaret D, DeWaal Malefijt R, Seiki M, Yoshida M, et al. Complete nucleotide sequence of the chromosomal gene for human IL-4 and its expression. J Immunol 1989, 142: 274–282.

    CAS  PubMed  Google Scholar 

  111. Marsh DG, Neely JD, Breazeale DR, Ghosh B, Friedhoff LR, Schou C, et al. Total serum IgE levels and chromosome 5q. Clin Exp Allergy 1995, 25 Suppl 2: 79–83; (discussion 95–76).

    Article  PubMed  Google Scholar 

  112. Kang HJ, Kim JM, Kim SW, Shin IS, Park SW, Kim YH, et al. Associations of cytokine genes with Alzheimer’s disease and depression in an elderly Korean population. J Neurol Neurosurg Psychiatry 2015, 86: 1002–1007.

    Article  PubMed  Google Scholar 

  113. Shibata N, Ohnuma T, Takahashi T, Baba H, Ishizuka T, Ohtsuka M, et al. The effect of IL4 +33C/T polymorphism on risk of Japanese sporadic Alzheimer’s disease. Neurosci Lett 2002, 323: 161–163.

    Article  CAS  PubMed  Google Scholar 

  114. Strle K, Zhou JH, Shen WH, Broussard SR, Johnson RW, Freund GG, et al. Interleukin-10 in the brain. Crit Rev Immunol 2001, 21: 427–449.

    Article  CAS  PubMed  Google Scholar 

  115. Kiyota T, Ingraham KL, Swan RJ, Jacobsen MT, Andrews SJ, Ikezu T. AAV serotype 2/1-mediated gene delivery of anti-inflammatory interleukin-10 enhances neurogenesis and cognitive function in APP + PS1 mice. Gene Ther 2012, 19: 724–733.

    Article  CAS  PubMed  Google Scholar 

  116. Chakrabarty P, Li A, Ceballos-Diaz C, Eddy JA, Funk CC, Moore B, et al. IL-10 alters immunoproteostasis in APP mice, increasing plaque burden and worsening cognitive behavior. Neuron 2015, 85: 519–533.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Lio D, Licastro F, Scola L, Chiappelli M, Grimaldi LM, Crivello A, et al. Interleukin-10 promoter polymorphism in sporadic Alzheimer’s disease. Genes Immun 2003, 4: 234–238.

    Article  CAS  PubMed  Google Scholar 

  118. Bagnoli S, Cellini E, Tedde A, Nacmias B, Piacentini S, Bessi V, et al. Association of IL10 promoter polymorphism in Italian Alzheimer’s disease. Neurosci Lett 2007, 418: 262–265.

    Article  CAS  PubMed  Google Scholar 

  119. Ma SL, Tang NL, Lam LC, Chiu HF. The association between promoter polymorphism of the interleukin-10 gene and Alzheimer’s disease. Neurobiol Aging 2005, 26: 1005–1010.

    Article  CAS  PubMed  Google Scholar 

  120. Medway C, Combarros O, Cortina-Borja M, Butler HT, Ibrahim-Verbaas CA, de Bruijn RF, et al. The sex-specific associations of the aromatase gene with Alzheimer’s disease and its interaction with IL10 in the Epistasis Project. Eur J Hum Genet 2014, 22: 216–220.

    Article  CAS  PubMed  Google Scholar 

  121. Rees LE, Wood NA, Gillespie KM, Lai KN, Gaston K, Mathieson PW. The interleukin-10-1082 G/A polymorphism: allele frequency in different populations and functional significance. Cell Mol Life Sci 2002, 59: 560–569.

    Article  CAS  PubMed  Google Scholar 

  122. Culpan D, Prince JA, Matthews S, Palmer L, Hughes A, Love S, et al. Neither sequence variation in the IL-10 gene promoter nor presence of IL-10 protein in the cerebral cortex is associated with Alzheimer’s disease. Neurosci Lett 2006, 408: 141–145.

    Article  CAS  PubMed  Google Scholar 

  123. Tesseur I, Zou K, Esposito L, Bard F, Berber E, Can JV, et al. Deficiency in neuronal TGF-beta signaling promotes neurodegeneration and Alzheimer’s pathology. J Clin Invest 2006, 116: 3060–3069.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Caraci F, Battaglia G, Busceti C, Biagioni F, Mastroiacovo F, Bosco P, et al. TGF-beta 1 protects against Abeta-neurotoxicity via the phosphatidylinositol-3-kinase pathway. Neurobiol Dis 2008, 30: 234–242.

    Article  CAS  PubMed  Google Scholar 

  125. Yokota M, Ichihara S, Lin TL, Nakashima N, Yamada Y. Association of a T29– > C polymorphism of the transforming growth factor-beta1 gene with genetic susceptibility to myocardial infarction in Japanese. Circulation 2000, 101: 2783–2787.

    Article  CAS  PubMed  Google Scholar 

  126. Chang WW, Zhang L, Jin YL, Yao YS. Meta-analysis of the transforming growth factor-beta1 polymorphisms and susceptibility to Alzheimer’s disease. J Neural Transm (Vienna) 2013, 120: 353–360.

    Article  CAS  Google Scholar 

  127. Shawkatova I, Javor J, Parnicka Z, Vrazda L, Novak M, Buc M. No association between cytokine gene polymorphism and risk of Alzheimer’s disease in Slovaks. Acta Neurobiol Exp (Wars) 2010, 70: 303–307.

    Google Scholar 

  128. Araria-Goumidi L, Lambert JC, Mann DM, Lendon C, Frigard B, Iwatsubo T, et al. Association study of three polymorphisms of TGF-beta1 gene with Alzheimer’s disease. J Neurol Neurosurg Psychiatry 2002, 73: 62–64.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Rodriguez-Rodriguez E, Sanchez-Juan P, Mateo I, Llorca J, Infante J, Garcia-Gorostiaga I, et al. Serum levels and genetic variation of TGF-beta1 are not associated with Alzheimer’s disease. Acta Neurol Scand 2007, 116: 409–412.

    Article  CAS  PubMed  Google Scholar 

  130. Singhal G, Jaehne EJ, Corrigan F, Toben C, Baune BT. Inflammasomes in neuroinflammation and changes in brain function: a focused review. Front Neurosci 2014, 8: 315.

    Article  PubMed  PubMed Central  Google Scholar 

  131. Mrak RE, Griffin WS. Glia and their cytokines in progression of neurodegeneration. Neurobiol Aging 2005, 26: 349–354.

    Article  CAS  PubMed  Google Scholar 

  132. Su F, Bai F, Zhou H, Zhang Z. Microglial toll-like receptors and Alzheimer’s disease. Brain Behav Immun 2016, 52: 187–198.

    Article  CAS  PubMed  Google Scholar 

  133. Colton C, Wilcock DM. Assessing activation states in microglia. CNS Neurol Disord Drug Targets 2010, 9: 174–191.

    Article  CAS  PubMed  Google Scholar 

  134. Grammas P, Ovase R. Inflammatory factors are elevated in brain microvessels in Alzheimer’s disease. Neurobiol Aging 2001, 22: 837–842.

    Article  CAS  PubMed  Google Scholar 

  135. Cacabelos R, Barquero M, Garcia P, Alvarez XA, Varela de Seijas E. Cerebrospinal fluid interleukin-1 beta (IL-1 beta) in Alzheimer’s disease and neurological disorders. Methods Find Exp Clin Pharmacol 1991, 13: 455–458.

    CAS  PubMed  Google Scholar 

  136. Li Y, Liu L, Barger SW, Griffin WS. Interleukin-1 mediates pathological effects of microglia on tau phosphorylation and on synaptophysin synthesis in cortical neurons through a p38-MAPK pathway. J Neurosci 2003, 23: 1605–1611.

    CAS  PubMed  PubMed Central  Google Scholar 

  137. Sheng JG, Zhu SG, Jones RA, Griffin WS, Mrak RE. Interleukin-1 promotes expression and phosphorylation of neurofilament and tau proteins in vivo. Exp Neurol 2000, 163: 388–391.

    Article  CAS  PubMed  Google Scholar 

  138. Nemeth H, Toldi J, Vecsei L. Role of kynurenines in the central and peripheral nervous systems. Curr Neurovasc Res 2005, 2: 249–260.

    Article  PubMed  Google Scholar 

  139. Rahman 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.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  140. Kettenmann H, Hanisch UK, Noda M, Verkhratsky A. Physiology of microglia. Physiol Rev 2011, 91: 461–553.

    Article  CAS  PubMed  Google Scholar 

  141. Caraci F, Battaglia G, Bruno V, Bosco P, Carbonaro V, Giuffrida ML, et al. TGF-beta1 pathway as a new target for neuroprotection in Alzheimer’s disease. CNS Neurosci Ther 2011, 17: 237–249.

    Article  CAS  PubMed  Google Scholar 

  142. Lambert JC, Ibrahim-Verbaas CA, Harold D, Naj AC, Sims R, Bellenguez C, et al. Meta-analysis of 74,046 individuals identifies 11 new susceptibility loci for Alzheimer’s disease. Nat Genet 2013, 45: 1452–1458.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  143. Chen JM, Jiang GX, Li QW, Zhou ZM, Cheng Q. Increased serum levels of interleukin-18, -23 and -17 in Chinese patients with Alzheimer’s disease. Dement Geriatr Cogn Disord 2014, 38: 321–329.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This review was partly supported by the National Natural Science Foundation of China (91332104 and 81201080); the Program for New Century Excellent Talents in University, China (NCET-13-0117); the Key Program for Clinical Medicine and Science and Technology of Jiangsu Province Clinical Medical Research Center, China (BL2013025); the Natural Science Foundation of Jiangsu Province, China (BK2012337); the National High-Tech R&D Program (863 Program) of China (SQ2015AA0200064); the Doctoral Fund of the Ministry of Education of China (20120092120068); and the Graduate Candidate Research Innovation Program of Jiangsu Province, China (KYLX15_0188).

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Feng Bai.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Su, F., Bai, F. & Zhang, Z. Inflammatory Cytokines and Alzheimer’s Disease: A Review from the Perspective of Genetic Polymorphisms. Neurosci. Bull. 32, 469–480 (2016). https://doi.org/10.1007/s12264-016-0055-4

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12264-016-0055-4

Keywords

Navigation