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Vol. 21, No. 2-3, 2014
Issue release date: February 2014
Neuroimmunomodulation 2014;21:79-87
(DOI:10.1159/000356529)

Innate Immune System and Inflammation in Alzheimer's Disease: From Pathogenesis to Treatment

Serpente M. · Bonsi R. · Scarpini E. · Galimberti D.
Neurology Unit, Department of Pathophysiology and Transplantation, University of Milan, Fondazione Cà Granda, IRCCS Ospedale Maggiore Policlinico, Milan, Italy

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Abstract

Immune activation and inflammation, likely triggered by amyloid-beta (Aβ) deposition, play a remarkable role in the pathogenesis of Alzheimer's disease (AD), which is the most frequent cause of dementia in the elderly. The principal cellular elements of the brain innate immune system likely to be involved in such processes are microglia. In an attempt to search for new disease-modifying drugs, the immune system has been addressed, with the aim of removing deposition of Aβ or tau by developing vaccines and humanized monoclonal antibodies. The aim of this review is to summarize the current evidence regarding the role played by microglia and inflammatory molecules in the pathogenesis of AD. In addition, we will discuss the main active and passive immunotherapeutic approaches. © 2014 S. Karger AG, Basel



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References

  1. Selkoe DJ: Translating cell biology into therapeutic advances in Alzheimer's disease. Nature 1999;399:A23-A31.
  2. Kang J, Lemaire HG, Unterbeck A, Salbaum JM, Masters CL, Grzeschik KH, Multhaup G, Beyreuther K, Müller-Hill B: The precursor of Alzheimer's disease amyloid A4 protein resembles a cell-surface receptor. Nature 1987;325:733-736
  3. Robert R, Wark KL: Engeneered antibody approaches for Alzheimer's disease immunotherapy. Arch Biochem Biophys 2012;132-138.
  4. Finch CE, Morgan TE: Systemic inflammation, infection, ApoE alleles, and Alzheimer disease: a position paper. Curr Alzheimer Res 2007;4:185-189.
  5. Tuppo EE, Arias HR: The role of inflammation in Alzheimer's disease. Int J Biochem Cell Biol 2005;37:289-305.
  6. Akiyama H, Barger S, Barnum S, et al: Inflammation and Alzheimer's disease. Neurobiol Aging 2000;21:383-421.
  7. Atwood CS, Obrenovich ME, Liu T, Chan H, Perry G, Smith MA, Martins RN: Amyloid-β: a chameleon walking in two worlds: a review of the trophic and toxic properties of amyloid-β. Brain Res Rev 2003;43:1-16.
  8. Bessis A, Bechade C, Bernard D, Roumier A: Microglial control of neuronal death and synaptic properties. Glia 2007;55:233-238.
  9. Kettenmann H, Hanisch UK, Noda M, Verkhratsky A: Physiology of microglia. Physiol Rev 2011;91:461-553.
  10. Dheen ST, Kaur C, Ling EA: Microglial activation and its implications in the brain diseases. Curr Med Chem 2007;14:1189-1197.
  11. Czeh M, Gressens P, Kaindl AM: The yin and yang of microglia. Dev Neurosci 2011;33:199-209.
  12. Pickford F, Marcus J, Camargo LM, Xiao Q, Graham D, Mo J, Burkhardt M, Kulkarni V, Crispino J, Hering H, Hutton H: Progranulin is a chemoattractant for microglia and stimulates their endocytic activity. Am J Pathol 2011;178:284-295.
  13. Combs CK, Karlo JC, Kao SC, Landreth GE: β-Amyloid stimulation of microglia anti monocytes results in TNFα-dependent expression of inducible nitric oxide synthase and neuronal apoptosis. J Neurosci 2001;21:1179-1188.

    External Resources

  14. Ho GJ, Drego R, Hakimian E, Masliah E: Mechanisms of cell signaling and inflammation in Alzheimer's disease. Curr Drug Targets Inflamm Allergy 2005;4:247-256.
  15. Verri M, Pastoris O, Dossena M, Aquilani R, Guerriero F, Cuzzoni G, Venturini L, Ricevuti G, Bongiorno AI: Mitochondrial alterations, oxidative stress and neuroinflammation in Alzheimer's disease. Int J Immunopathol Pharmacol 2012;25:345-353.

    External Resources

  16. Li C, Zhao R, Gao K, Wei Z, Yin MY, Lau LT, Chui D, Hoi Yu AC: Astrocytes: implications for neuroinflammatory pathogenesis of Alzheimer's disease. Curr Alzheimer Res 2011;8:67-80.
  17. Schousboe A, Westergaard N, Sonnerwald U, Petersen SB, Yu AC, L: Hertz: Regulatory role of astrocytes for neuronal biosynthesis and homeostasis of glutamate and GABA. Prog Brain Res 1992;94:199-211.

    External Resources

  18. Aloisi F: Cytokine production; in Kettnman H, Ransom B (eds): Neuroglia. Oxford, Oxford University, 2005, pp 285-301.
  19. Strack A, Asensio VC, Campbell IL, Schluter D, Deckert M: Chemokines are differentially expressed by astrocytes, microglia and inflammatory leukocytes in Toxoplasma encephalitis and critically regulated by interferon-γ. Acta Neuropathol 2002;103:458-468.
  20. Maccioni RB, Rojo LE, Fernandez JA, Kuljis RO: The role of neuroimmunomodulation in Alzheimer's disease. Ann N Y Acad Sci 2009;1153:240-246.
  21. Blasko I, Veerhuis R, Stampfer-Kountchev M, Saurwein-Teissl M, Eikelenboom P, Grubeck-Loebenstein B: Costimulatory effects of interferon-γ and interleukin-1β or tumor necrosis factor-α on the synthesis of Aβ1-40 and Aβ1-42 by human astrocytes. Neurobiol Dis 2000;7:682-689.
  22. White JA, Manelli AM, Holmberg KH, Van Eldik LJ, Ladu MJ: Differential effects of oligomeric and fibrillar amyloid-β1-42 on astrocyte-mediated inflammation. Neurobiol Dis 2005;18:459-465.
  23. Friedman WJ: Cytokines regulate expression of the type 1 interleuken-1 receptor in rat hippocampal neurons and glia. Exp Neurol 2001;168:23-31.
  24. Li Y, Barger SW, Liu L, Mrak RE, Griffin WST: S100-β induction of the pro-inflammatory cytokine interleukin-6 in neurons: implications for Alzheimer pathogenesis. J Neurochem 2000;74:143-150.
  25. Renauld AE, Spengler RN: Tumor necrosis factor expressed by primary hippocampal neurons SH-SY5Y cells is regulated by α2-adrenergic receptor activation. J Neurosci Res 2002;67:264-274.
  26. Walker D, McGeer E, McGeer P: Involvement of inflammation and complement in Alzheimer's disease: Clinical Neuroimmunology. Oxford, Blackwell Scientific, 1997, pp 172-188.
  27. McGeer E, McGeer P: Inflammatory cytokines in the CNS. CNS Drugs 1997;7:214-287.
  28. Blasko I, Marx F, Steiner E, Hartmann T, Grubeck-Loebenstein B: TNFα plus IFNγ induce the production of Alzheimer β-amyloid peptides and decrease the secretion of APPs. FASEB J 1999;13:63-68.

    External Resources

  29. Eikelenboom P, Van Gool WA: Neuroinflammatory perspectives on the two faces of Alzheimer's disease. J Neural Transm 2004;111:281-294.
  30. Mrak RE, Griffin WST: Interleukin-1, neuroinflammation, and Alzheimer's disease. Neurobiol Aging 2001;22:903-908.
  31. Mackenzie IR: Anti-inflammatory drugs and Alzheimer type pathologyin aging. Neurology 2000;54:732-734.
  32. Benveniste EN: Cytokine actions in the central nervous system. Cytokine Growth Factor Rev 1998;9:259-275.
  33. Selmaj KW, Farooq M, Norton WT, Raine CS, Brosnan CF: Proliferation of astrocytes in vitro in response to cytokines: a primary role for tumor necrosis factor. J Immunol 1990;144:129-135.

    External Resources

  34. Heyser CJ, Masliah E, Samimi A, Campbell IL, Gold LH: Progressive decline in avoidance learning paralleled by inflammatory neurodegeneration in transgenic mice expressing interleukin 6 in the brain. Proc Natl Acad Sci USA 1997;94:1500-1505.
  35. Van Wagoner NJ, Oh JW, Repovic P, Benveniste EN: IL-6 (IL-6) production by astrocytes: autocrine regulation by IL-6 and the soluble IL-6 receptor. J Neurosci 1999;19:5236-5244.

    External Resources

  36. Smith JA, Das A, Ray SK, Banik NL: Role of pro-inflammatory cytokines released from microglia in neurodegenerative diseases. Brain Res Bull 2012;87:10-20.
  37. Galimberti D, Venturelli E, Fenoglio C, Guidi I, Villa C, Bergamaschini L, Cortini F, Scalabrini D, Baron P, Vergani C, Bresolin N, Scarpini E: Intrathecal levels of IL-6, IL-11 and LIF in Alzheimer's disease and frontotemporal lobar degeneration. J Neurol 2008;255:539-544.
  38. Owens T, Babcock AA, Millward JM, Toft-Hansen H: Cytokine and chemokine inter-regulation in the inflamed or injured CNS. Brain Res Rev 2005;48:178-184.
  39. Xia M, Hyman BT: Chemokines/chemokine receptors in the central nervous system and Alzheimer's disease. J Neurovirol 1999;5:32-41.
  40. Lue LF, Rydel RE, Brigham EF, Yang LB, Hampel H, Murphy GM, Brachova L, Yan SD, Walker DG, Shen Y, Rogers J: Inflammatory repertoire of Alzheimer's disease and nondemented elderly microglia in vitro. Glia 2001;35:72-79.
  41. Xia MQ, Qin SX, Wu LJ, Mackay CR, Hyman BT: Immunohistochemical study of the β-chemokine receptors CCR3 and CCR5 and their ligands in normal and Alzheimer's disease brains. Am J Pathol 1998;153:31-37.
  42. Galimberti D, Schoonenboom N, Scheltens P, Fenoglio C, Bouwman F, Venturelli E, Guidi I, Blankenstein MA, Bresolin N, Scarpini E: Intrathecal chemokine synthesis in mild cognitive impairment and Alzheimer disease. Arch Neurol 2006;63:538-543.
  43. Delrieu J, Piau A, Caillaud C, Voisin T, Vellas B: Managing cognitive dysfunction through the continuum of Alzheimer's disease: role of pharmacotherapy. CNS Drugs 2011;25:213-226.
  44. McGeer PL, Schulzer M, McGeer EG: Arthritis and anti-inflammatory agents as possible protective factors for Alzheimer's disease: a review of 17 epidemiologic studies. Neurology 1996;47:425-432.
  45. Galimberti D, Scarpini E: Progress in Alzheimer's disease. J Neurol 2012;259:201-211.
  46. Fu HJ, Liu B, Frost JL, Lemere CA: Amyloid-β immunotherapy for Alzheimer's disease. CNS Neurol Disord Drug Targets 2010;9:197-206.
  47. Morgan D: Immunotherapy for Alzheimer's disease. J Alzheimer Dis 2006;9:425-432.

    External Resources

  48. Solomon B, Koppel R, Hanan E, Katzav T: Monoclonal antibodies inhibit in vitro fibrillar aggregation of the Alzheimer β-amyloid peptide. Proc Natl Acad Sci USA 1996;93:452-455.
  49. Schenk D, Barbour R, Dunn W, Gordon G, Grajeda H, Guido T, Hu K, Huang J, Johnson-Wood K, Khan K, Kholodenko D, Lee M, Liao Z, Lieberburg I, Motter R, Mutter L, Soriano F, Shopp G, Vasquez N, Vandevert C, Walker S, Wogulis M, Yednock T, Games D, Seubert P: Immunization with amyloid-β attenuates Alzheimer-disease-like pathology in the PDAPP mouse. Nature 1999;400:173-177.
  50. Janus C, Pearson J, McLaurin J, Mathews PM, Jiang Y, Schmidt SD, Chishti MA, Horne P, Heslin D, French J, Mount HT, Nixon RA, Mercken M, Bergeron C, Fraser PE, St George-Hyslop P, Westaway D: Aβ peptide immunization reduces behavioural impairment and plaques in a model of Alzheimer's disease. Nature 2000;408:979-982.
  51. Bard F, Cannon C, Barbour R, Burke RL, Games D, Grajeda H, Guido T, Hu K, Huang J, Johnson-Wood K, Khan K, Kholodenko D, Lee M, Lieberburg I, Motter R, Nguyen M, Soriano F, Vasquez N, Weiss K, Welch B, Seubert P, Schenk D, Yednock T: Peripherally administered antibodies against amyloid β-peptide enter the central nervous system and reduce pathology in a mouse model of Alzheimer disease. Nat Med 2000;6:916-919.
  52. Lobello K, Ryan MJ, Liu E, Rippon G, Black R: Targeting beta amyloid: a clinical review of immunotherapic approaches in Alzheimer's disease. Int J Alzheimers Dis 2012;2012:628070.
  53. Bayer AJ, Bullock R, Jones RW, Wilkinson D, Paterson KR, Jenkins L, Millais SB, Donoghue S: Evaluation of the safety and immunogenicity of synthetic Aβ42 (AN1792) in patients with AD. Neurology 2005;64:94-101.
  54. Nicoll JA, Barton E, Boche D, Neal JW, Ferrer I, Thompson P, Vlachouli C, Wilkinson D, Bayer A, Games D, Seubert P, Schenk D, Holmes C: Aβ species removal after aβ42 immunization. J Neuropathol Exp Neurol 2006;65:1040-1048.
  55. Holmes C, Boche D, Wilkinson D, Yadegarfar G, Hopkins V, Bayer A, Jones RW, Bullock R, Love S, Neal JW, Zotova E, Nicoll JA: Long-term effects of Aβ42 immunisation in Alzheimer's disease: follow-up of a randomised, placebo-controlled phase I trial. Lancet 2008;372:216-223.
  56. Galimberti D, Ghezzi L, Scarpini E: Immunotherapy against amyloid pathology in Alzheimer's disease. J Neurol Sci 2013;333:50-54.
  57. Pfeifer M, Boncristiano S, Bondolfi L, Stalder A, Deller T, Staufenbiel M, Mathews PM, Jucker M: Cerebral hemorrhage after passive anti-Aβ immunotherapy. Science 2002;298:1379.
  58. Kerchner GA, Boxer AL: Bapineuzumab. Expert Opin Biol Ther 2010;10:1121-1130.
  59. Samadi H, Sultzer D: Solanezumab for Alzheimer's disease. Expert Opin Biol Ther 2011;11:787-798.
  60. Robert R, Lefranc MP, Ghochikyan A, Agadjanyan MG, Cribbs DH, Van Nostrand WE, Wark KL, Dolezal O: Restricted V gene usage and VH/VL pairing of mouse humoral response against the N-terminal immunodominant epitope of the amyloid β peptide. Mol Immunol 2010;48:59-72.
  61. Wilcock DM, Alamed J, Gottschall PE, Grimm J, Rosenthal A, Pons J, Ronan V, Symmonds K, Gordon MN, Morgan D: Deglycosylated anti-amyloid-beta antibodies eliminate cognitive deficits and reduce parenchymal amyloid with minimal vascular consequences in aged amyloid precursor protein transgenic mice. J Neurosci 2006;26:5340-5346.
  62. Das P, Howard V, Loosbrock N, Dickson D, Murphy MP, Golde TE: Amyloid-β immunization effectively reduces amyloid deposition in FcRγ-/- knock-out mice. J Neurosci 2003;23:8532-8538.

    External Resources

  63. Wang YJ, Zhou HD, Zhou XF: Modified immunotherapies against Alzheimer's disease: toward safer and effective amyloid clearance. J Alzheimers Dis 2010;21:1065-1075.
  64. Robert R, Wark KL: Engineered antibody approaches for Alzheimer's disease immunotherapy. Arch Biochem Biophys 2012;526:132-138.
  65. Magga J, Puli L, Pihlaja R, Kanninen K, Neulamaa S, Malm T, Härtig W, Grosche J, Goldsteins G, Tanila H, Koistinaho J, Koistinaho M: Human intravenous immunoglobulin provides protection against Aβ toxicity by multiple mechanisms in a mouse model of Alzheimer's disease. J Neuroinflammation 2010;7;7:90.
  66. Dodel R, Rominger A, Bartenstein P, Barkhof F, Blennow K, Förster S, Winter Y, Bach JP, Popp J, Alferink J, Wiltfang J, Buerger K, Otto M, Antuono P, Jacoby M, Richter R, Stevens J, Melamed I, Goldstein J, Haag S, Wietek S, Farlow M, Jessen F: Intravenous immunoglobulin for treatment of mild-to-moderate Alzheimer's disease: a phase 2, randomised, double-blind, placebo-controlled, dose-finding trial. Lancet Neurol 2013;12:233-243.
  67. Himmelstein DS, Ward SM, Lancia JK, Patterson KR, Binder LI: Tau as a therapeutic target in neurodegenerative disease. Pharmacol Ther 2012;136:8-22 Review.
  68. Rosenmann H, Grigoriadis N, Karussis D, Boimel M, Touloumi O, Ovadia H, Abramsky O: Tauopathy-like abnormalities and neurologic deficits in mice immunized with neuronal tau protein. Arch Neurol 2006;63:1459-1467.
  69. Boutajangout A, Quartermain D, Sigurdsson EM: Immunotherapy targeting pathological tau prevents cognitive decline in a new tangle mouse model. J Neurosci 2010;30:16559-16566.
  70. Chai X, Wu S, Murray TK, Kinley R, Cella CV, Sims H, Buckner N, Hanmer J, Davies P, O'Neill MJ, Hutton ML, Citron M: Passive immunization with anti-Tau antibodies in two transgenic models: reduction of Tau pathology and delay of disease progression. J Biol Chem 2011;286:34457-34467.
  71. Hyman BT: Amyloid-dependent and amyloid-independent stages of Alzheimer disease. Arch Neurol 2011;68:1062-1064.


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