Journal of Neuroimmune Pharmacology

, Volume 10, Issue 4, pp 547–560 | Cite as

T Cells—Protective or Pathogenic in Alzheimer’s Disease?

  • Róisín M. McManus
  • Kingston H. G. Mills
  • Marina A. Lynch
INVITED REVIEW

Abstract

Alzheimer’s disease (AD) is the most common cause of dementia, and is characterised by deposits of amyloid β (Aβ), neurofibrillary tangles and neuronal loss. Neuroinflammatory changes have been identified as a feature of the disease, and recent studies have suggested a potential role for the peripheral immune system in driving these changes and, ultimately, the associated neuronal degeneration. A number of reports have detailed changes in the activation state and subtype of T cells in the circulation and CSF of AD patients and there is evidence of T cell infiltration into the brain. In this review, we examine the possible impact of T cell infiltration in the progression of pathology in AD and consider the data obtained from animal models of the disease. We consider how these cells infiltrate the brain, particularly in AD, and discuss whether the presence of T cells in the AD brain is protective or pathogenic. Finally we evaluate the current therapies, particularly those that involve immunization.

Keywords

Alzheimer’s disease T cell Microglia Astrocyte Amyloid β Neuroinflammation 

Notes

Acknowledgments

This work was supported by grants from Science Foundation Ireland to KHGM (11/PI/1036) and MAL (11/PI/10154) and an Innovation Bursary (to KHGM and MAL from Trinity College Dublin).

Conflict of Interest

Kingston Mills is a co-founder and shareholder in Opsona Therapeutics Ltd and TriMod Therapeutics Ltd, university spin-out companies involved in the development of immunotherapeutics.

References

  1. Agrawal S, Anderson P, Durbeej M, van Rooijen N, Ivars F, Opdenakker G, Sorokin LM (2006) Dystroglycan is selectively cleaved at the parenchymal basement membrane at sites of leukocyte extravasation in experimental autoimmune encephalomyelitis. J Exp Med 203:1007–1019PubMedCentralPubMedCrossRefGoogle Scholar
  2. Akiyama H, Ikeda K, Kondo H, McGeer PL (1992) Thrombin accumulation in brains of patients with Alzheimer’s disease. Neurosci Lett 146:152–154PubMedCrossRefGoogle Scholar
  3. Akiyama H, Kawamata T, Yamada T, Tooyama I, Ishii T, McGeer PL (1993) Expression of intercellular adhesion molecule (ICAM)-1 by a subset of astrocytes in Alzheimer disease and some other degenerative neurological disorders. Acta Neuropathol 85:628–634PubMedCrossRefGoogle Scholar
  4. 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 21:383–421PubMedCentralPubMedCrossRefGoogle Scholar
  5. Aloisi F, Ria F, Penna G, Adorini L (1998) Microglia are more efficient than astrocytes in antigen processing and in Th1 but not Th2 cell activation. J Immunol 160:4671–4680PubMedGoogle Scholar
  6. Aloisi F, De Simone R, Columba-Cabezas S, Penna G, Adorini L (2000) Functional maturation of adult mouse resting microglia into an APC is promoted by granulocyte-macrophage colony-stimulating factor and interaction with Th1 cells. J Immunol 164:1705–1712PubMedCrossRefGoogle Scholar
  7. Archambault AS, Sim J, Gimenez MA, Russell JH (2005) Defining antigen-dependent stages of T cell migration from the blood to the central nervous system parenchyma. Eur J Immunol 35:1076–1085PubMedCrossRefGoogle Scholar
  8. Asahi M, Wang X, Mori T, Sumii T, Jung JC, Moskowitz MA, Fini ME, Lo EH (2001) Effects of matrix metalloproteinase-9 gene knock-out on the proteolysis of blood-brain barrier and white matter components after cerebral ischemia. J Neurosci 21:7724–7732PubMedGoogle Scholar
  9. Asuni AA, Boutajangout A, Scholtzova H, Knudsen E, Li YS, Quartermain D, Frangione B, Wisniewski T, Sigurdsson EM (2006) Vaccination of Alzheimer’s model mice with Abeta derivative in alum adjuvant reduces Abeta burden without microhemorrhages. Eur J Neurosci 24:2530–2542PubMedCentralPubMedCrossRefGoogle Scholar
  10. Babcock AA, Ilkjaer B, Clausen BH, Villadsen B, Dissing-Olesen L, Bendixen AT, Lyck L, Lambertsen KL, Finsen B (2015) Cytokine-producing microglia have an altered beta-amyloid load in aged APP/PS1 Tg mice. Brain Behav ImmunGoogle Scholar
  11. Baglio F, Saresella M, Preti MG, Cabinio M, Griffanti L, Marventano I, Piancone F, Calabrese E, Nemni R, Clerici M (2013) Neuroinflammation and brain functional disconnection in Alzheimer’s disease. Front Aging Neurosci 5:81PubMedCentralPubMedCrossRefGoogle Scholar
  12. Bateman RJ, Xiong C, Benzinger TL, Fagan AM, Goate A, Fox NC, Marcus DS, Cairns NJ, Xie X, Blazey TM, Holtzman DM, Santacruz A, Buckles V, Oliver A, Moulder K, Aisen PS, Ghetti B, Klunk WE, McDade E, Martins RN, Masters CL, Mayeux R, Ringman JM, Rossor MN, Schofield PR, Sperling RA, Salloway S, Morris JC (2012) Clinical and biomarker changes in dominantly inherited Alzheimer’s disease. N Engl J Med 367:795–804PubMedCentralPubMedCrossRefGoogle Scholar
  13. Bell RD, Winkler EA, Singh I, Sagare AP, Deane R, Wu Z, Holtzman DM, Betsholtz C, Armulik A, Sallstrom J, Berk BC, Zlokovic BV (2012) Apolipoprotein E controls cerebrovascular integrity via cyclophilin A. Nature 485:512–516PubMedCentralPubMedCrossRefGoogle Scholar
  14. Bergers G, Song S (2005) The role of pericytes in blood-vessel formation and maintenance. Neuro Oncol 7:452–464PubMedCentralPubMedCrossRefGoogle Scholar
  15. Berzin TM, Zipser BD, Rafii MS, Kuo-Leblanc V, Yancopoulos GD, Glass DJ, Fallon JR, Stopa EG (2000) Agrin and microvascular damage in Alzheimer’s disease. Neurobiol Aging 21:349–355PubMedCrossRefGoogle Scholar
  16. Biron KE, Dickstein DL, Gopaul R, Jefferies WA (2011) Amyloid triggers extensive cerebral angiogenesis causing blood brain barrier permeability and hypervascularity in Alzheimer’s disease. PLoS One 6:e23789PubMedCentralPubMedCrossRefGoogle Scholar
  17. Boche D, Nicoll JA (2008) The role of the immune system in clearance of Abeta from the brain. Brain Pathol 18:267–278PubMedCrossRefGoogle Scholar
  18. Bolton SJ, Anthony DC, Perry VH (1998) Loss of the tight junction proteins occludin and zonula occludens-1 from cerebral vascular endothelium during neutrophil-induced blood-brain barrier breakdown in vivo. Neuroscience 86:1245–1257PubMedCrossRefGoogle Scholar
  19. Boven LA, Middel J, Verhoef J, De Groot CJ, Nottet HS (2000) Monocyte infiltration is highly associated with loss of the tight junction protein zonula occludens in HIV-1-associated dementia. Neuropathol Appl Neurobiol 26:356–360PubMedCrossRefGoogle Scholar
  20. Bowman CC, Rasley A, Tranguch SL, Marriott I (2003) Cultured astrocytes express toll-like receptors for bacterial products. Glia 43:281–291PubMedCrossRefGoogle Scholar
  21. Brosseron F, Krauthausen M, Kummer M, Heneka MT (2014) Body fluid cytokine levels in mild cognitive impairment and Alzheimer’s disease: a comparative overview. Mol Neurobiol 50:534–544PubMedCentralPubMedCrossRefGoogle Scholar
  22. Browne TC, McQuillan K, McManus RM, O’Reilly JA, Mills KH, Lynch MA (2013) IFN-γ production by amyloid β-specific Th1 cells promotes microglial activation and increases plaque burden in a mouse model of Alzheimer’s disease. J Immunol 190:2241–2251PubMedCrossRefGoogle Scholar
  23. Butovsky O, Talpalar AE, Ben-Yaakov K, Schwartz M (2005) Activation of microglia by aggregated beta-amyloid or lipopolysaccharide impairs MHC-II expression and renders them cytotoxic whereas IFN-gamma and IL-4 render them protective. Mol Cell Neurosci 29:381–393, United States PubMedCrossRefGoogle Scholar
  24. Butovsky O, Koronyo-Hamaoui M, Kunis G, Ophir E, Landa G, Cohen H, Schwartz M (2006) Glatiramer acetate fights against Alzheimer’s disease by inducing dendritic-like microglia expressing insulin-like growth factor 1. Proc Natl Acad Sci U S A 103:11784–11789PubMedCentralPubMedCrossRefGoogle Scholar
  25. Calingasan NY, Erdely HA, Altar CA (2002) Identification of CD40 ligand in Alzheimer’s disease and in animal models of Alzheimer’s disease and brain injury. Neurobiol Aging 23:31–39PubMedCrossRefGoogle Scholar
  26. Campbell M, Kiang AS, Kenna PF, Kerskens C, Blau C, O’Dwyer L, Tivnan A, Kelly JA, Brankin B, Farrar GJ, Humphries P (2008) RNAi-mediated reversible opening of the blood-brain barrier. J Gene Med 10:930–947PubMedCrossRefGoogle Scholar
  27. Cao C, Arendash GW, Dickson A, Mamcarz MB, Lin X, Ethell DW (2009) Abeta-specific Th2 cells provide cognitive and pathological benefits to Alzheimer’s mice without infiltrating the CNS. Neurobiol Dis 34:63–70PubMedCrossRefGoogle Scholar
  28. Carare RO, Bernardes-Silva M, Newman TA, Page AM, Nicoll JA, Perry VH, Weller RO (2008) Solutes, but not cells, drain from the brain parenchyma along basement membranes of capillaries and arteries: significance for cerebral amyloid angiopathy and neuroimmunology. Neuropathol Appl Neurobiol 34:131–144PubMedCrossRefGoogle Scholar
  29. Carrano A, Hoozemans JJ, van der Vies SM, Rozemuller AJ, van Horssen J, de Vries HE (2011) Amyloid Beta induces oxidative stress-mediated blood-brain barrier changes in capillary amyloid angiopathy. Antioxid Redox Signal 15:1167–1178PubMedCrossRefGoogle Scholar
  30. Carter SL, Muller M, Manders PM, Campbell IL (2007) Induction of the genes for Cxcl9 and Cxcl10 is dependent on IFN-gamma but shows differential cellular expression in experimental autoimmune encephalomyelitis and by astrocytes and microglia in vitro. Glia 55:1728–1739PubMedCrossRefGoogle Scholar
  31. Cartier L, Hartley O, Dubois-Dauphin M, Krause KH (2005) Chemokine receptors in the central nervous system: role in brain inflammation and neurodegenerative diseases. Brain Res Brain Res Rev 48:16–42PubMedCrossRefGoogle Scholar
  32. Chastain EM, Duncan DS, Rodgers JM, Miller SD (2011) The role of antigen presenting cells in multiple sclerosis. Biochim Biophys Acta 1812:265–274PubMedCentralPubMedCrossRefGoogle Scholar
  33. Constantinescu CS, Tani M, Ransohoff RM, Wysocka M, Hilliard B, Fujioka T, Murphy S, Tighe PJ, Das Sarma J, Trinchieri G, Rostami A (2005) Astrocytes as antigen-presenting cells: expression of IL-12/IL-23. J Neurochem 95:331–340PubMedCrossRefGoogle Scholar
  34. Cornejo F, von Bernhardi R (2013) Role of scavenger receptors in glia-mediated neuroinflammatory response associated with Alzheimer’s disease. Mediators Inflamm 2013, 895651PubMedCentralPubMedCrossRefGoogle Scholar
  35. Cribbs DH, Ghochikyan A, Vasilevko V, Tran M, Petrushina I, Sadzikava N, Babikyan D, Kesslak P, Kieber-Emmons T, Cotman CW, Agadjanyan MG (2003) Adjuvant-dependent modulation of Th1 and Th2 responses to immunization with beta-amyloid. Int Immunol 15:505–514PubMedCentralPubMedCrossRefGoogle Scholar
  36. Denieffe S, Kelly RJ, McDonald C, Lyons A, Lynch MA (2013) Classical activation of microglia in CD200-deficient mice is a consequence of blood brain barrier permeability and infiltration of peripheral cells. Brain Behav Immun 34:86–97PubMedCrossRefGoogle Scholar
  37. Dong Y, Benveniste EN (2001) Immune function of astrocytes. Glia 36:180–190PubMedCrossRefGoogle Scholar
  38. Engelhardt B, Ransohoff RM (2005) The ins and outs of T-lymphocyte trafficking to the CNS: anatomical sites and molecular mechanisms. Trends Immunol 26:485–495PubMedCrossRefGoogle Scholar
  39. Engelhardt B, Ransohoff RM (2012) Capture, crawl, cross: the T cell code to breach the blood-brain barriers. Trends Immunol 33:579–589PubMedCrossRefGoogle Scholar
  40. Engelhardt B, Wolburg-Buchholz K, Wolburg H (2001) Involvement of the choroid plexus in central nervous system inflammation. Microsc Res Tech 52:112–129PubMedCrossRefGoogle Scholar
  41. Farrall AJ, Wardlaw JM (2009) Blood-brain barrier: ageing and microvascular disease—systematic review and meta-analysis. Neurobiol Aging 30:337–352PubMedCrossRefGoogle Scholar
  42. Fiala M, Zhang L, Gan X, Sherry B, Taub D, Graves MC, Hama S, Way D, Weinand M, Witte M, Lorton D, Kuo YM, Roher AE (1998) Amyloid-beta induces chemokine secretion and monocyte migration across a human blood–brain barrier model. Mol Med 4:480–489PubMedCentralPubMedGoogle Scholar
  43. 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 Investig 32:360–371CrossRefGoogle Scholar
  44. Fiala M, Lin J, Ringman J, Kermani-Arab V, Tsao G, Patel A, Lossinsky AS, Graves MC, Gustavson A, Sayre J, Sofroni E, Suarez T, Chiappelli F, Bernard G (2005) Ineffective phagocytosis of amyloid-beta by macrophages of Alzheimer’s disease patients. J Alzheimers Dis 7:221–232, discussion 255-62 PubMedGoogle Scholar
  45. Fisher Y, Strominger I, Biton S, Nemirovsky A, Baron R, Monsonego A (2014) Th1 polarization of T cells injected into the cerebrospinal fluid induces brain immunosurveillance. J Immunol 192:92–102PubMedCrossRefGoogle Scholar
  46. Fletcher JM, Lalor SJ, Sweeney CM, Tubridy N, Mills KH (2010) T cells in multiple sclerosis and experimental autoimmune encephalomyelitis. Clin Exp Immunol 162:1–11PubMedCentralPubMedCrossRefGoogle Scholar
  47. Frackowiak J, Wisniewski HM, Wegiel J, Merz GS, Iqbal K, Wang KC (1992) Ultrastructure of the microglia that phagocytose amyloid and the microglia that produce beta-amyloid fibrils. Acta Neuropathol 84:225–233PubMedCrossRefGoogle Scholar
  48. Fuhrmann M, Bittner T, Jung CK, Burgold S, Page RM, Mitteregger G, Haass C, LaFerla FM, Kretzschmar H, Herms J (2010) Microglial Cx3cr1 knockout prevents neuron loss in a mouse model of Alzheimer’s disease. Nat Neurosci 13:411–413PubMedCentralPubMedCrossRefGoogle Scholar
  49. Girvin AM, Gordon KB, Welsh CJ, Clipstone NA, Miller SD (2002) Differential abilities of central nervous system resident endothelial cells and astrocytes to serve as inducible antigen-presenting cells. Blood 99:3692–3701PubMedCrossRefGoogle Scholar
  50. Goldeck D, Larbi A, Pellicano M, Alam I, Zerr I, Schmidt C, Fulop T, Pawelec G (2013) Enhanced chemokine receptor expression on leukocytes of patients with Alzheimer’s disease. PLoS One 8:e66664PubMedCentralPubMedCrossRefGoogle Scholar
  51. Greter M, Heppner FL, Lemos MP, Odermatt BM, Goebels N, Laufer T, Noelle RJ, Becher B (2005) Dendritic cells permit immune invasion of the CNS in an animal model of multiple sclerosis. Nat Med 11:328–334PubMedCrossRefGoogle Scholar
  52. Harkness KA, Adamson P, Sussman JD, Davies-Jones GA, Greenwood J, Woodroofe MN (2000) Dexamethasone regulation of matrix metalloproteinase expression in CNS vascular endothelium. Brain 123(Pt 4):698–709Google Scholar
  53. Hartwig M (1995) Immune ageing and Alzheimer’s disease. Neuroreport 6:1274–1276PubMedCrossRefGoogle Scholar
  54. Hickey WF (2001) Basic principles of immunological surveillance of the normal central nervous system. Glia 36:118–124PubMedCrossRefGoogle Scholar
  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 (2008) Long-term effects of Abeta42 immunisation in Alzheimer’s disease: follow-up of a randomised, placebo-controlled phase I trial. Lancet 372:216–223PubMedCrossRefGoogle Scholar
  56. Jack CS, Arbour N, Manusow J, Montgrain V, Blain M, McCrea E, Shapiro A, Antel JP (2005) TLR signaling tailors innate immune responses in human microglia and astrocytes. J Immunol 175:4320–4330PubMedCrossRefGoogle Scholar
  57. 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 (2000) A beta peptide immunization reduces behavioural impairment and plaques in a model of Alzheimer’s disease. Nature 408:979–982PubMedCrossRefGoogle Scholar
  58. Jimenez S, Baglietto-Vargas D, Caballero C, Moreno-Gonzalez I, Torres M, Sanchez-Varo R, Ruano D, Vizuete M, Gutierrez A, Vitorica J (2008) Inflammatory response in the hippocampus of PS1M146L/APP751SL mouse model of Alzheimer’s disease: age-dependent switch in the microglial phenotype from alternative to classic. J Neurosci 28:11650–11661PubMedCrossRefGoogle Scholar
  59. Jones RS, Minogue AM, Connor TJ, Lynch MA (2013) Amyloid-β-induced astrocytic phagocytosis is mediated by CD36, CD47 and RAGE. J Neuroimmune Pharmacol 8:301–311PubMedCrossRefGoogle Scholar
  60. Kawanokuchi J, Shimizu K, Nitta A, Yamada K, Mizuno T, Takeuchi H, Suzumura A (2008) Production and functions of IL-17 in microglia. J Neuroimmunol 194:54–61PubMedCrossRefGoogle Scholar
  61. Kebir H, Kreymborg K, Ifergan I, Dodelet-Devillers A, Cayrol R, Bernard M, Giuliani F, Arbour N, Becher B, Prat A (2007) Human TH17 lymphocytes promote blood-brain barrier disruption and central nervous system inflammation. Nat Med 13:1173–1175PubMedCrossRefGoogle Scholar
  62. Kelly RJ, Minogue AM, Lyons A, Jones RS, Browne TC, Costello DA, Denieffe S, O’Sullivan C, Connor TJ, Lynch MA (2013) Glial activation in A beta PP/PS1 mice is associated with infiltration of IFN gamma-producing cells. J Alzheimers Dis 37:63–75Google Scholar
  63. Kirk J, Plumb J, Mirakhur M, McQuaid S (2003) Tight junctional abnormality in multiple sclerosis white matter affects all calibres of vessel and is associated with blood-brain barrier leakage and active demyelination. J Pathol 201:319–327PubMedCrossRefGoogle Scholar
  64. Kivisakk P, Mahad DJ, Callahan MK, Trebst C, Tucky B, Wei T, Wu L, Baekkevold ES, Lassmann H, Staugaitis SM, Campbell JJ, Ransohoff RM (2003) Human cerebrospinal fluid central memory CD4+ T cells: evidence for trafficking through choroid plexus and meninges via P-selectin. Proc Natl Acad Sci U S A 100:8389–8394PubMedCentralPubMedCrossRefGoogle Scholar
  65. Koenigsknecht-Talboo J, Landreth GE (2005) Microglial phagocytosis induced by fibrillar beta-amyloid and IgGs are differentially regulated by proinflammatory cytokines. J Neurosci 25:8240–8249PubMedCrossRefGoogle Scholar
  66. Kook SY, Hong HS, Moon M, Ha CM, Chang S, Mook-Jung I (2012) Abeta(1)(-)(4)(2)-RAGE interaction disrupts tight junctions of the blood-brain barrier via Ca(2)(+)-calcineurin signaling. J Neurosci 32:8845–8854PubMedCrossRefGoogle Scholar
  67. Kort JJ, Kawamura K, Fugger L, Weissert R, Forsthuber TG (2006) Efficient presentation of myelin oligodendrocyte glycoprotein peptides but not protein by astrocytes from HLA-DR2 and HLA-DR4 transgenic mice. J Neuroimmunol 173:23–34PubMedCrossRefGoogle Scholar
  68. Lambracht-Washington D, Rosenberg RN (2013) Anti-amyloid beta to tau - based immunization: Developments in immunotherapy for Alzheimer disease. Immunotargets Ther 2013:105–114PubMedCentralPubMedCrossRefGoogle Scholar
  69. Lambracht-Washington D, Rosenberg RN (2015) Co-stimulation with TNF receptor superfamily 4/25 antibodies enhances in-vivo expansion of CD4+CD25+Foxp3+ T cells (Tregs) in a mouse study for active DNA Abeta42 immunotherapy. J Neuroimmunol 278:90–99PubMedPubMedCentralCrossRefGoogle Scholar
  70. Lambracht-Washington D, Qu BX, Fu M, Anderson LD Jr, Stuve O, Eagar TN, Rosenberg RN (2011) DNA immunization against amyloid beta 42 has high potential as safe therapy for Alzheimer’s disease as it diminishes antigen-specific Th1 and Th17 cell proliferation. Cell Mol Neurobiol 31:867–874PubMedCentralPubMedCrossRefGoogle Scholar
  71. Laporte V, Ait-Ghezala G, Volmar CH, Mullan M (2006) CD40 deficiency mitigates Alzheimer’s disease pathology in transgenic mouse models. J Neuroinflammation 3:3PubMedCentralPubMedCrossRefGoogle Scholar
  72. Larbi A, Pawelec G, Witkowski JM, Schipper HM, Derhovanessian E, Goldeck D, Fulop T (2009) Dramatic shifts in circulating CD4 but not CD8 T cell subsets in mild Alzheimer’s disease. J Alzheimers Dis 17:91–103PubMedGoogle Scholar
  73. Leech S, Kirk J, Plumb J, McQuaid S (2007) Persistent endothelial abnormalities and blood-brain barrier leak in primary and secondary progressive multiple sclerosis. Neuropathol Appl Neurobiol 33:86–98PubMedCrossRefGoogle Scholar
  74. Li M, Shang DS, Zhao WD, Tian L, Li B, Fang WG, Zhu L, Man SM, Chen YH (2009) Amyloid beta interaction with receptor for advanced glycation end products up-regulates brain endothelial CCR5 expression and promotes T cells crossing the blood-brain barrier. J Immunol 182:5778–5788PubMedCrossRefGoogle Scholar
  75. Liu YJ, Guo DW, Tian L, Shang DS, Zhao WD, Li B, Fang WG, Zhu L, Chen YH (2010) Peripheral T cells derived from Alzheimer’s disease patients overexpress CXCR2 contributing to its transendothelial migration, which is microglial TNF-alpha-dependent. Neurobiol Aging 31:175–188PubMedCrossRefGoogle Scholar
  76. Liu S, Shi D, Wang HC, Yu YZ, Xu Q, Sun ZW (2015) Co-immunization with DNA and protein mixture: a safe and efficacious immunotherapeutic strategy for Alzheimer’s disease in PDAPP mice. Sci Rep 5:7771PubMedCentralPubMedCrossRefGoogle Scholar
  77. Lorenzl S, Albers DS, Relkin N, Ngyuen T, Hilgenberg SL, Chirichigno J, Cudkowicz ME, Beal MF (2003) Increased plasma levels of matrix metalloproteinase-9 in patients with Alzheimer’s disease. Neurochem Int 43:191–196PubMedCrossRefGoogle Scholar
  78. Lueg G, Gross CC, Lohmann H, Johnen A, Kemmling A, Deppe M, Groger J, Minnerup J, Wiendl H, Meuth SG, Duning T (2015) Clinical relevance of specific T-cell activation in the blood and cerebrospinal fluid of patients with mild Alzheimer’s disease. Neurobiol Aging 36:81–89PubMedCrossRefGoogle Scholar
  79. Ma X, Reynolds SL, Baker BJ, Li X, Benveniste EN, Qin H (2010) IL-17 enhancement of the IL-6 signaling cascade in astrocytes. J Immunol 184:4898–4906PubMedCentralPubMedCrossRefGoogle Scholar
  80. Man SM, Ma YR, Shang DS, Zhao WD, Li B, Guo DW, Fang WG, Zhu L, Chen YH (2007) Peripheral T cells overexpress MIP-1alpha to enhance its transendothelial migration in Alzheimer’s disease. Neurobiol Aging 28:485–496PubMedCrossRefGoogle Scholar
  81. Marco S, Skaper SD (2006) Amyloid beta-peptide1-42 alters tight junction protein distribution and expression in brain microvessel endothelial cells. Neurosci Lett 401:219–224PubMedCrossRefGoogle Scholar
  82. McGeer PL, Itagaki S, Tago H, McGeer EG (1987) Reactive microglia in patients with senile dementia of the Alzheimer type are positive for the histocompatibility glycoprotein HLA-DR. Neurosci Lett 79:195–200PubMedCrossRefGoogle Scholar
  83. McGeer PL, Akiyama H, Itagaki S, McGeer EG (1989) Immune system response in Alzheimer’s disease. Can J Neurol Sci 16:516–527PubMedGoogle Scholar
  84. McManus RM, Higgins SC, Mills KH, Lynch MA (2014) Respiratory infection promotes T cell infiltration and amyloid-beta deposition in APP/PS1 mice. Neurobiol Aging 35:109–121PubMedCrossRefGoogle Scholar
  85. McMenamin PG (1999) Distribution and phenotype of dendritic cells and resident tissue macrophages in the dura mater, leptomeninges, and choroid plexus of the rat brain as demonstrated in wholemount preparations. J Comp Neurol 405:553–562PubMedCrossRefGoogle Scholar
  86. McQuillan K, Lynch MA, Mills KH (2010) Activation of mixed glia by Abeta-specific Th1 and Th17 cells and its regulation by Th2 cells. Brain Behav Immun 24:598–607PubMedCrossRefGoogle Scholar
  87. Merlini M, Meyer EP, Ulmann-Schuler A, Nitsch RM (2011) Vascular beta-amyloid and early astrocyte alterations impair cerebrovascular function and cerebral metabolism in transgenic arcAbeta mice. Acta Neuropathol 122:293–311PubMedCentralPubMedCrossRefGoogle Scholar
  88. Miljkovic D, Momcilovic M, Stojanovic I, Stosic-Grujicic S, Ramic Z, Mostarica-Stojkovic M (2007) Astrocytes stimulate interleukin-17 and interferon-gamma production in vitro. J Neurosci Res 85:3598–3606PubMedCrossRefGoogle Scholar
  89. Minagar A, Alexander JS (2003) Blood-brain barrier disruption in multiple sclerosis. Mult Scler 9:540–549PubMedCrossRefGoogle Scholar
  90. Minogue AM, Jones RS, Kelly RJ, McDonald CL, Connor TJ, Lynch MA (2014) Age-associated dysregulation of microglial activation is coupled with enhanced blood-brain barrier permeability and pathology in APP/PS1 mice. Neurobiol Aging 35:1442–1452PubMedCrossRefGoogle Scholar
  91. Moalem G, Leibowitz-Amit R, Yoles E, Mor F, Cohen IR, Schwartz M (1999) Autoimmune T cells protect neurons from secondary degeneration after central nervous system axotomy. Nat Med 5:49–55PubMedCrossRefGoogle Scholar
  92. Monson NL, Ireland SJ, Ligocki AJ, Chen D, Rounds WH, Li M, Huebinger RM, Munro Cullum C, Greenberg BM, Stowe AM, Zhang R (2014) Elevated CNS inflammation in patients with preclinical Alzheimer’s disease. J Cereb Blood Flow Metab 34:30–33PubMedCentralPubMedCrossRefGoogle Scholar
  93. Monsonego A, Zota V, Karni A, Krieger JI, Bar-Or A, Bitan G, Budson AE, Sperling R, Selkoe DJ, Weiner HL (2003) Increased T cell reactivity to amyloid beta protein in older humans and patients with Alzheimer disease. J Clin Invest 112:415–422PubMedCentralPubMedCrossRefGoogle Scholar
  94. Murphy AC, Lalor SJ, Lynch MA, Mills KH (2010) Infiltration of Th1 and Th17 cells and activation of microglia in the CNS during the course of experimental autoimmune encephalomyelitis. Brain Behav Immun 24:641–651PubMedCrossRefGoogle Scholar
  95. Nair A, Frederick TJ, Miller SD (2008) Astrocytes in multiple sclerosis: a product of their environment. Cell Mol Life Sci 65:2702–2720PubMedCentralPubMedCrossRefGoogle Scholar
  96. Nicoll JA, Yamada M, Frackowiak J, Mazur-Kolecka B, Weller RO (2004) Cerebral amyloid angiopathy plays a direct role in the pathogenesis of Alzheimer’s disease. Pro-CAA position statement. Neurobiol Aging 25:589–597, discussion 603-4 PubMedCrossRefGoogle Scholar
  97. Nikcevich KM, Gordon KB, Tan L, Hurst SD, Kroepfl JF, Gardinier M, Barrett TA, Miller SD (1997) IFN-gamma-activated primary murine astrocytes express B7 costimulatory molecules and prime naive antigen-specific T cells. J Immunol 158:614–621PubMedGoogle Scholar
  98. Nitta T, Hata M, Gotoh S, Seo Y, Sasaki H, Hashimoto N, Furuse M, Tsukita S (2003) Size-selective loosening of the blood-brain barrier in claudin-5-deficient mice. J Cell Biol 161:653–660PubMedCentralPubMedCrossRefGoogle Scholar
  99. Olkhanud PB, Mughal M, Ayukawa K, Malchinkhuu E, Bodogai M, Feldman N, Rothman S, Lee JH, Chigurupati S, Okun E, Nagashima K, Mattson MP, Biragyn A (2012) DNA immunization with HBsAg-based particles expressing a B cell epitope of amyloid β-peptide attenuates disease progression and prolongs survival in a mouse model of Alzheimer’s disease. Vaccine 30:1650–1658PubMedCentralPubMedCrossRefGoogle Scholar
  100. Olson JK, Miller SD (2004) Microglia initiate central nervous system innate and adaptive immune responses through multiple TLRs. J Immunol 173:3916–3924PubMedCrossRefGoogle Scholar
  101. Olson JK, Girvin AM, Miller SD (2001) Direct activation of innate and antigen-presenting functions of microglia following infection with Theiler’s virus. J Virol 75:9780–9789PubMedCentralPubMedCrossRefGoogle Scholar
  102. Owens T, Bechmann I, Engelhardt B (2008) Perivascular spaces and the two steps to neuroinflammation. J Neuropathol Exp Neurol 67:1113–1121PubMedCrossRefGoogle Scholar
  103. Pan XD, Zhu YG, Lin N, Zhang J, Ye QY, Huang HP, Chen XC (2011) Microglial phagocytosis induced by fibrillar beta-amyloid is attenuated by oligomeric beta-amyloid: implications for Alzheimer’s disease. Mol Neurodegener 6:45PubMedCentralPubMedCrossRefGoogle Scholar
  104. Panossian LA, Porter VR, Valenzuela HF, Zhu X, Reback E, Masterman D, Cummings JL, Effros RB (2003) Telomere shortening in T cells correlates with Alzheimer’s disease status. Neurobiol Aging 24:77–84PubMedCrossRefGoogle Scholar
  105. Parachikova A, Agadjanyan MG, Cribbs DH, Blurton-Jones M, Perreau V, Rogers J, Beach TG, Cotman CW (2007) Inflammatory changes parallel the early stages of Alzheimer disease. Neurobiol Aging 28:1821–1833PubMedCentralPubMedCrossRefGoogle Scholar
  106. Pellicano M, Bulati M, Buffa S, Barbagallo M, Di Prima A, Misiano G, Picone P, Di Carlo M, Nuzzo D, Candore G, Vasto S, Lio D, Caruso C, Colonna-Romano G (2010) Systemic immune responses in Alzheimer’s disease: in vitro mononuclear cell activation and cytokine production. J Alzheimers Dis 21:181–192PubMedGoogle Scholar
  107. Pellicano M, Larbi A, Goldeck D, Colonna-Romano G, Buffa S, Bulati M, Rubino G, Iemolo F, Candore G, Caruso C, Derhovanessian E, Pawelec G (2012) Immune profiling of Alzheimer patients. J Neuroimmunol 242:52–59PubMedCrossRefGoogle Scholar
  108. Perlmutter LS, Scott SA, Barron E, Chui HC (1992) MHC class II-positive microglia in human brain: association with Alzheimer lesions. J Neurosci Res 33:549–558PubMedCrossRefGoogle Scholar
  109. Pfeifer M, Boncristiano S, Bondolfi L, Stalder A, Deller T, Staufenbiel M, Mathews PM, Jucker M (2002) Cerebral hemorrhage after passive anti-Abeta immunotherapy. Science 298:1379PubMedCrossRefGoogle Scholar
  110. Pirttila T, Mattinen S, Frey H (1992) The decrease of CD8-positive lymphocytes in Alzheimer’s disease. J Neurol Sci 107:160–165PubMedCrossRefGoogle Scholar
  111. Plumb J, McQuaid S, Mirakhur M, Kirk J (2002) Abnormal endothelial tight junctions in active lesions and normal-appearing white matter in multiple sclerosis. Brain Pathol 12:154–169PubMedCrossRefGoogle Scholar
  112. Prajeeth CK, Lohr K, Floess S, Zimmermann J, Ulrich R, Gudi V, Beineke A, Baumgartner W, Muller M, Huehn J, Stangel M (2014) Effector molecules released by Th1 but not Th17 cells drive an M1 response in microglia. Brain Behav Immun 37:248–259PubMedCrossRefGoogle Scholar
  113. Reale M, Iarlori C, Feliciani C, Gambi D (2008) Peripheral chemokine receptors, their ligands, cytokines and Alzheimer’s disease. J Alzheimers Dis 14:147–159PubMedGoogle Scholar
  114. Reboldi A, Coisne C, Baumjohann D, Benvenuto F, Bottinelli D, Lira S, Uccelli A, Lanzavecchia A, Engelhardt B, Sallusto F (2009) C-C chemokine receptor 6-regulated entry of TH-17 cells into the CNS through the choroid plexus is required for the initiation of EAE. Nat Immunol 10:514–523PubMedCrossRefGoogle Scholar
  115. Rock RB, Hu S, Deshpande A, Munir S, May BJ, Baker CA, Peterson PK, Kapur V (2005) Transcriptional response of human microglial cells to interferon-gamma. Genes Immun 6:712–719PubMedGoogle Scholar
  116. 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 9:339–349PubMedCrossRefGoogle Scholar
  117. Rollins BJ (1997) Chemokines. Blood 90:909–928PubMedGoogle Scholar
  118. Ryu JK, McLarnon JG (2009) A leaky blood-brain barrier, fibrinogen infiltration and microglial reactivity in inflamed Alzheimer’s disease brain. J Cell Mol Med 13:2911–2925PubMedCentralPubMedCrossRefGoogle Scholar
  119. Saresella M, Calabrese E, Marventano I, Piancone F, Gatti A, Calvo MG, Nemni R, Clerici M (2010) PD1 negative and PD1 positive CD4+ T regulatory cells in mild cognitive impairment and Alzheimer’s disease. J Alzheimers Dis 21:927–938PubMedGoogle Scholar
  120. Saresella M, Calabrese E, Marventano I, Piancone F, Gatti A, Alberoni M, Nemni R, Clerici M (2011) Increased activity of Th-17 and Th-9 lymphocytes and a skewing of the post-thymic differentiation pathway are seen in Alzheimer’s disease. Brain Behav Immun 25:539–547PubMedCrossRefGoogle Scholar
  121. Saresella M, Calabrese E, Marventano I, Piancone F, Gatti A, Farina E, Alberoni M, Clerici M (2012) A potential role for the PD1/PD-L1 pathway in the neuroinflammation of Alzheimer’s disease. Neurobiol Aging 33:624.e11–22CrossRefGoogle Scholar
  122. Sarma JD, Ciric B, Marek R, Sadhukhan S, Caruso ML, Shafagh J, Fitzgerald DC, Shindler KS, Rostami A (2009) Functional interleukin-17 receptor A is expressed in central nervous system glia and upregulated in experimental autoimmune encephalomyelitis. J Neuroinflammation 6:14PubMedCentralPubMedCrossRefGoogle Scholar
  123. Schenk D (2002) Amyloid-beta immunotherapy for Alzheimer’s disease: the end of the beginning. Nat Rev Neurosci 3:824–828PubMedCrossRefGoogle Scholar
  124. 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 (1999) Immunization with amyloid-beta attenuates Alzheimer-disease-like pathology in the PDAPP mouse. Nature 400:173–177PubMedCrossRefGoogle Scholar
  125. Schindowski K, Eckert A, Peters J, Gorriz C, Schramm U, Weinandi T, Maurer K, Frölich L, Müller WE (2007) Increased T-cell reactivity and elevated levels of CD8+ memory T-cells in Alzheimer’s disease-patients and T-cell hyporeactivity in an Alzheimer’s disease-mouse model: implications for immunotherapy. Neuromol Med 9:340–354CrossRefGoogle Scholar
  126. Schwartz M, Baruch K (2014) The resolution of neuroinflammation in neurodegeneration: leukocyte recruitment via the choroid plexus. EMBO J 33:7–22PubMedCentralPubMedCrossRefGoogle Scholar
  127. Séguin R, Biernacki K, Prat A, Wosik K, Kim HJ, Blain M, McCrea E, Bar-Or A, Antel JP (2003) Differential effects of Th1 and Th2 lymphocyte supernatants on human microglia. Glia 42:36–45PubMedCrossRefGoogle Scholar
  128. Shimizu E, Kawahara K, Kajizono M, Sawada M, Nakayama H (2008) IL-4-induced selective clearance of oligomeric beta-amyloid peptide(1-42) by rat primary type 2 microglia. J Immunol 181:6503–6513PubMedCrossRefGoogle Scholar
  129. Smits HA, van Beelen AJ, de Vos NM, Rijsmus A, van der Bruggen T, Verhoef J, van Muiswinkel FL, Nottet HS (2001) Activation of human macrophages by amyloid-beta is attenuated by astrocytes. J Immunol 166:6869–6876PubMedCrossRefGoogle Scholar
  130. Soos JM, Ashley TA, Morrow J, Patarroyo JC, Szente BE, Zamvil SS (1999) Differential expression of B7 co-stimulatory molecules by astrocytes correlates with T cell activation and cytokine production. Int Immunol 11:1169–1179PubMedCrossRefGoogle Scholar
  131. Speciale L, Calabrese E, Saresella M, Tinelli C, Mariani C, Sanvito L, Longhi R, Ferrante P (2007) Lymphocyte subset patterns and cytokine production in Alzheimer’s disease patients. Neurobiol Aging 28:1163–1169PubMedCrossRefGoogle Scholar
  132. Streit WJ, Conde JR, Harrison JK (2001) Chemokines and Alzheimer’s disease. Neurobiol Aging 22:909–913PubMedCrossRefGoogle Scholar
  133. Tai LM, Holloway KA, Male DK, Loughlin AJ, Romero IA (2010) Amyloid-beta-induced occludin down-regulation and increased permeability in human brain endothelial cells is mediated by MAPK activation. J Cell Mol Med 14:1101–1112PubMedCentralPubMedGoogle Scholar
  134. Tan L, Gordon KB, Mueller JP, Matis LA, Miller SD (1998) Presentation of proteolipid protein epitopes and B7-1-dependent activation of encephalitogenic T cells by IFN-gamma-activated SJL/J astrocytes. J Immunol 160:4271–4279PubMedGoogle Scholar
  135. Tan J, Town T, Paris D, Mori T, Suo Z, Crawford F, Mattson MP, Flavell RA, Mullan M (1999) Microglial activation resulting from CD40-CD40L interaction after beta-amyloid stimulation. Science 286:2352–2355PubMedCrossRefGoogle Scholar
  136. Tan J, Town T, Crawford F, Mori T, DelleDonne A, Crescentini R, Obregon D, Flavell RA, Mullan MJ (2002) Role of CD40 ligand in amyloidosis in transgenic Alzheimer’s mice. Nat Neurosci 5:1288–1293PubMedCrossRefGoogle Scholar
  137. Teige I, Liu Y, Issazadeh-Navikas S (2006) IFN-beta inhibits T cell activation capacity of central nervous system APCs. J Immunol 177:3542–3553PubMedCrossRefGoogle Scholar
  138. Togo T, Akiyama H, Kondo H, Ikeda K, Kato M, Iseki E, Kosaka K (2000) Expression of CD40 in the brain of Alzheimer’s disease and other neurological diseases. Brain Res 885:117–121PubMedCrossRefGoogle Scholar
  139. Togo T, Akiyama H, Iseki E, Kondo H, Ikeda K, Kato M, Oda T, Tsuchiya K, Kosaka K (2002) Occurrence of T cells in the brain of Alzheimer’s disease and other neurological diseases. J Neuroimmunol 124:83–92PubMedCrossRefGoogle Scholar
  140. Town T, Tan J, Flavell RA, Mullan M (2005) T-cells in Alzheimer’s disease. Neuromol Med 7:255–264CrossRefGoogle Scholar
  141. Townsend KP, Town T, Mori T, Lue LF, Shytle D, Sanberg PR, Morgan D, Fernandez F, Flavell RA, Tan J (2005) CD40 signaling regulates innate and adaptive activation of microglia in response to amyloid beta-peptide. Eur J Immunol 35:901–910PubMedCrossRefGoogle Scholar
  142. Tran EH, Hoekstra K, van Rooijen N, Dijkstra CD, Owens T (1998) Immune invasion of the central nervous system parenchyma and experimental allergic encephalomyelitis, but not leukocyte extravasation from blood, are prevented in macrophage-depleted mice. J Immunol 161:3767–3775PubMedGoogle Scholar
  143. Tripathy D, Thirumangalakudi L, Grammas P (2007) Expression of macrophage inflammatory protein 1-alpha is elevated in Alzheimer’s vessels and is regulated by oxidative stress. J Alzheimers Dis 11:447–455PubMedGoogle Scholar
  144. Tripathy D, Thirumangalakudi L, Grammas P (2010) RANTES upregulation in the Alzheimer’s disease brain: a possible neuroprotective role. Neurobiol Aging 31:8–16PubMedCentralPubMedCrossRefGoogle Scholar
  145. Van Itallie CM, Fanning AS, Bridges A, Anderson JM (2009) ZO-1 stabilizes the tight junction solute barrier through coupling to the perijunctional cytoskeleton. Mol Biol Cell 20:3930–3940PubMedCentralPubMedCrossRefGoogle Scholar
  146. Van Wagoner NJ, Oh JW, Repovic P, Benveniste EN (1999) Interleukin-6 (IL-6) production by astrocytes: autocrine regulation by IL-6 and the soluble IL-6 receptor. J Neurosci 19:5236–5244PubMedGoogle Scholar
  147. Vellas B, Black R, Thal LJ, Fox NC, Daniels M, McLennan G, Tompkins C, Leibman C, Pomfret M, Grundman M; for the AN1792 (QS-21)-251 Study Team (2009) Long-term follow-up of patients immunized with AN1792: reduced functional decline in antibody responders. Curr Alzheimer Res 6:144–151Google Scholar
  148. Viggars AP, Wharton SB, Simpson JE, Matthews FE, Brayne C, Savva GM, Garwood C, Drew D, Shaw PJ, Ince PG (2011) Alterations in the blood brain barrier in ageing cerebral cortex in relationship to Alzheimer-type pathology: a study in the MRC-CFAS population neuropathology cohort. Neurosci Lett 505:25–30PubMedCrossRefGoogle Scholar
  149. Vom Berg J, Prokop S, Miller KR, Obst J, Kalin RE, Lopategui-Cabezas I, Wegner A, Mair F, Schipke CG, Peters O, Winter Y, Becher B, Heppner FL (2012) Inhibition of IL-12/IL-23 signaling reduces Alzheimer’s disease-like pathology and cognitive decline. Nat Med 18:1812–1819PubMedCrossRefGoogle Scholar
  150. Weiner HL, Lemere CA, Maron R, Spooner ET, Grenfell TJ, Mori C, Issazadeh S, Hancock WW, Selkoe DJ (2000) Nasal administration of amyloid-beta peptide decreases cerebral amyloid burden in a mouse model of Alzheimer’s disease. Ann Neurol 48:567–579PubMedCrossRefGoogle Scholar
  151. Weiss N, Miller F, Cazaubon S, Couraud PO (2009) The blood-brain barrier in brain homeostasis and neurological diseases. Biochim Biophys Acta 1788:842–857PubMedCrossRefGoogle Scholar
  152. Wilcock DM, Colton CA (2008) Anti-amyloid-beta immunotherapy in Alzheimer’s disease: relevance of transgenic mouse studies to clinical trials. J Alzheimers Dis 15:555–569PubMedCentralPubMedGoogle Scholar
  153. Wilcock DM, Vitek MP, Colton CA (2009) Vascular amyloid alters astrocytic water and potassium channels in mouse models and humans with Alzheimer’s disease. Neuroscience 159:1055–1069PubMedCentralPubMedCrossRefGoogle Scholar
  154. Wolf SA, Gimsa U, Bechmann I, Nitsch R (2001) Differential expression of costimulatory molecules B7-1 and B7-2 on microglial cells induced by Th1 and Th2 cells in organotypic brain tissue. Glia 36:414–420PubMedCrossRefGoogle Scholar
  155. Wolf SA, Fisher J, Bechmann I, Steiner B, Kwidzinski E, Nitsch R (2002) Neuroprotection by T-cells depends on their subtype and activation state. J Neuroimmunol 133:72–80PubMedCrossRefGoogle Scholar
  156. Wraith DC, Nicholson LB (2012) The adaptive immune system in diseases of the central nervous system. J Clin Invest 122:1172–1179PubMedCentralPubMedCrossRefGoogle Scholar
  157. Xia MQ, Qin SX, Wu LJ, Mackay CR, Hyman BT (1998) Immunohistochemical study of the beta-chemokine receptors CCR3 and CCR5 and their ligands in normal and Alzheimer’s disease brains. Am J Pathol 153:31–37PubMedCentralPubMedCrossRefGoogle Scholar
  158. Xia MQ, Bacskai BJ, Knowles RB, Qin SX, Hyman BT (2000) Expression of the chemokine receptor CXCR3 on neurons and the elevated expression of its ligand IP-10 in reactive astrocytes: in vitro ERK1/2 activation and role in Alzheimer’s disease. J Neuroimmunol 108:227–235PubMedCrossRefGoogle Scholar
  159. Zeinstra E, Wilczak N, Streefland C, De Keyser J (2000) Astrocytes in chronic active multiple sclerosis plaques express MHC class II molecules. Neuroreport 11:89–91PubMedCrossRefGoogle Scholar
  160. Zeinstra E, Wilczak N, De Keyser J (2003) Reactive astrocytes in chronic active lesions of multiple sclerosis express co-stimulatory molecules B7-1 and B7-2. J Neuroimmunol 135:166–171PubMedCrossRefGoogle Scholar
  161. Zipser BD, Johanson CE, Gonzalez L, Berzin TM, Tavares R, Hulette CM, Vitek MP, Hovanesian V, Stopa EG (2007) Microvascular injury and blood-brain barrier leakage in Alzheimer’s disease. Neurobiol Aging 28:977–986PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2015

Authors and Affiliations

  • Róisín M. McManus
    • 1
    • 2
  • Kingston H. G. Mills
    • 2
  • Marina A. Lynch
    • 1
  1. 1.Trinity College Institute of NeuroscienceTrinity Biomedical Sciences Institute, Trinity College DublinDublin 2Ireland
  2. 2.School of Biochemistry and ImmunologyTrinity Biomedical Sciences Institute, Trinity College DublinDublin 2Ireland

Personalised recommendations