NeuroMolecular Medicine

, Volume 9, Issue 4, pp 340–354 | Cite as

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

  • Katharina SchindowskiEmail author
  • Anne Eckert
  • Jürgen Peters
  • Corinna Gorriz
  • Uta Schramm
  • Thomas Weinandi
  • Konrad Maurer
  • Lutz Frölich
  • Walter E. Müller
Original Paper


Neuroinflammation is observed in neurodegenerative diseases like Alzheimer’s disease (AD). However, a little is known about the mechanisms of neural-immune interactions. The involvement of peripheral T-cell function in AD is still far from clear, though it plays an important role in immunotherapy. The aim of this study was to determine peripheral T-cell reactivity in AD patients and in an AD mouse model. Mitogenic activation via ligation of the T-cell receptor (TCR) with PHA-L was measured in T lymphocytes from AD patients and Thy1(APP751SL) × HMG(PS1M146L)-transgenic mice (APP × PS1). In order to uncover failures in TCR signaling, the TCR was also bypassed by PMA and ionomycin treatment. All patients were sporadic late onset cases and the transgenic mice expressed no mutant APP in lymphocytes, so that direct interactions of mutant APP on T-cell function can be excluded. CD4+ and CD8+ T-cell showed increased reactivity (tyrosine phosphorylation, CD69 expression, and proliferation) in AD, while APP × PS1 transgenic mice displayed hyporeactive CD8+ T-cells after TCR ligation. Increased levels of CD8+ T memory cells and down regulation of CD8 receptor were found in AD and the animal model. Anergic TCR uncoupling was associated with loss of MAPK signaling (p38, ERK1 and ERK2) in APP × PS1. Our data implicate the generation of reactive memory T-cell in AD and of anergic memory T-cells in transgenic mice and should be taken into concern when designing immunotherapy.


Neurodegeneration CD3 Activation-induced cell death (AICD) CD69 BrdU 4G10 Apoliporotein E (ApoE) Neuroinflammation Hyposensitive Neural–immune interaction 



7-Amino actinomycin


Alzheimer’s disease


Apoliporotein E


Amyloid precursor protein




Cluster of differentiation


Central nervous system


Fluorescein isothiocyanate


Forward scatter




Mini mental state examination score


Mitogen-activated protein kinase


Multiple sclerosis


Not statistically significant


Not determined


Peripheral blood mononuclear cells




Peridin chlorophyll


Lectin from Phaseolus vulgaris Leucoagglutinin


Phorbol 12-myristate 13-acetate




Side scatter


T helper





This work was supported by grants from Dr. Robert Pfleger Stiftung, Alzheimer Initiative e.V., Hirnliga e.V. and a Marie-Curie fellowship to KS. Disclosure statement: This study was approved by the responsible Ethical Committee and in accordance with standards of the guide for the care and use of laboratory animals and with respect to European Community rules.


  1. Adunsky, A., Baram, D., Hershkowitz, M., & Mekori, Y. A. (1991). Increased cytosolic free calcium in lymphocytes of Alzheimer patients. Journal of Neuroimmunology, 33, 167–172.PubMedGoogle Scholar
  2. Adunsky, A., Diver-Haber, A., Becker, D., & Hershkowitz, M. (1995). Basal and activated intracellular calcium ion concentrations in mononuclear cells of Alzheimer’s disease and unipolar depression. The Journals of Gerontology. Series A Biological Sciences and Medical Sciences, 50, B201–B204.Google Scholar
  3. Aloisi, F., Ria, F., Columba-Cabezas, S., Hess, H., Penna, G., & Adorini, L. (1999). Relative efficiency of microglia, astrocytes, dendritic cells and B cells in naive CD4+ T cell priming and Th1/Th2 cell restimulation. European Journal of Immunology, 29, 2705–2714.PubMedGoogle Scholar
  4. Blanchard, V., Moussaoui, S., Czech, C., Touchet, N., Bonici, B., Planche, M., Canton, T., Jedidi, I., Gohin, M., Wirths, O., Bayer, T. A., Langui, D., Duyckaerts, C., Tremp, G., & Pradier, L. (2003). Time sequence of maturation of dystrophic neurites associated with Abeta deposits in APP/PS1 transgenic mice. Experimental Neurology, 184, 247–263.PubMedGoogle Scholar
  5. Bongioanni, P., Boccardi, B., Borgna, M., Castagna, M., & Mondino, C. (1997a). T-cell interferon gamma binding in patients with dementia of the Alzheimer type. Archives of Neurology, 54, 457–462.PubMedGoogle Scholar
  6. Bongioanni, P., Boccardi, B., Borgna, M., & Rossi, B. (1998). T-lymphocyte interleukin 6 receptor binding in patients with dementia of Alzheimer type. Archives of Neurology, 55, 1305–1308.PubMedGoogle Scholar
  7. Bongioanni, P., Romano, M. R., Sposito, R., Castagna, M., Boccardi, B., & Borgna, M. (1997b). T-cell tumour necrosis factor-alpha receptor binding in demented patients. Journal of Neurology, 244, 418–425.PubMedGoogle Scholar
  8. Carson, M. J., Reilly, C. R., Sutcliffe, J. G., & Lo, D. (1999). Disproportionate recruitment of CD8+ T cells into the central nervous system by professional antigen-presenting cells. American Journal of Pathology, 154, 481–494.PubMedGoogle Scholar
  9. Carson, M. J., & Sutcliffe, J. G. (1999). Balancing function vs. self defense: The CNS as an active regulator of immune responses. Journal of Neuroscience Research, 55, 1–8.PubMedGoogle Scholar
  10. Chandok, M. R., & Farber, D. L. (2004). Signaling control of memory T cell generation and function. Seminars in Immunology, 16, 285–293.PubMedGoogle Scholar
  11. Chiodetti, L., Choi, S., Barber, D. L., & Schwartz, R. H. (2006). Adaptive tolerance and clonal anergy are distinct biochemical states. Journal of Immunology, 176, 2279–2291.Google Scholar
  12. Cho, B. K., Wang, C., Sugawa, S., Eisen, H. N., & Chen, J. (1999). Functional differences between memory and naive CD8 T cells. Proceedings of the National Academy of Sciences of the United States of America, 96, 2976–2981.PubMedGoogle Scholar
  13. Colton, C. A., Brown, C. M., & Vitek, M. P. (2005). Sex steroids, APOE genotype and the innate immune system. Neurobiology of Aging, 26, 363–372.PubMedGoogle Scholar
  14. Cornet, A., Bettelli, E., Oukka, M., Cambouris, C., Avellana-Adalid, V., Kosmatopoulos, K., & Liblau, R. S. (2000). Role of astrocytes in antigen presentation and naive T-cell activation. Journal of Neuroimmunology, 106, 69–77.PubMedGoogle Scholar
  15. Cribbs, D. H., Ghochikyan, A., Vasilevko, V., Tran, M., Petrushina, I., Sadzikava, N., Babikyan, D., Kesslak, P., Kieber-Emmons, T., Cotman, C. W., & Agadjanyan, M. G. (2003). Adjuvant-dependent modulation of Th1 and Th2 responses to immunization with beta-amyloid. International Immunology, 15, 505–514.PubMedGoogle Scholar
  16. Czech, C., Delaere, P., Macq, A. F., Reibaud, M., Dreisler, S., Touchet, N., Schombert, B., Mazadier, M., Mercken, L., Theisen, M., Pradier, L., Octave, J. N., Beyreuther, K., & Tremp, G. (1997). Proteolytical processing of mutated human amyloid precursor protein in transgenic mice. Brain Research. Molecular Brain Research, 47, 108–116.PubMedGoogle Scholar
  17. Dai, Z., Nasr, I. W., Reel, M., Deng, S., Diggs, L., Larsen, C. P., Rothstein, D. M., & Lakkis, F. G. (2005). Impaired recall of CD8 memory T cells in immunologically privileged tissue. Journal of Immunology, 174, 1165–1170.Google Scholar
  18. Das, P., Murphy, M. P., Younkin, L. H., Younkin, S. G., & Golde, T. E. (2001). Reduced effectiveness of Abeta1-42 immunization in APP transgenic mice with significant amyloid deposition. Neurobiology of Aging, 22, 721–727.PubMedGoogle Scholar
  19. DeSilva, D. R., Feeser, W. S., Tancula, E. J., & Scherle, P. A. (1996). Anergic T cells are defective in both jun NH2-terminal kinase and mitogen-activated protein kinase signaling pathways. The Journal of Experimental Medicine, 183, 2017–2023.PubMedGoogle Scholar
  20. DeSilva, D. R., Jones, E. A., Feeser, W. S., Manos, E. J., & Scherle, P. A. (1997). The p38 mitogen-activated protein kinase pathway in activated and anergic Th1 cells. Cellular Immunology, 180, 116–123.PubMedGoogle Scholar
  21. Dorszewska, J., Florczak, J., Rozycka, A., Jaroszewska-Kolecka, J., Trzeciak, W. H., & Kozubski, W. (2005). Polymorphisms of the CHRNA4 gene encoding the alpha4 subunit of nicotinic acetylcholine receptor as related to the oxidative DNA damage and the level of apoptotic proteins in lymphocytes of the patients with Alzheimer’s disease. DNA and Cell Biology, 24, 786–794.PubMedGoogle Scholar
  22. Duff, K., Eckman, C., Zehr, C., Yu, X., Prada, C. M., Perez-tur, J., Hutton, M., Buee, L., Harigaya, Y., Yager, D., Morgan, D., Gordon, M. N., Holcomb, L., Refolo, L., Zenk, B., Hardy, J., & Younkin, S. (1996). Increased amyloid-beta42(43) in brains of mice expressing mutant presenilin 1. Nature, 383, 710–713.PubMedGoogle Scholar
  23. Ebstein, R. P., Nemanov, L., Lubarski, G., Dano, M., Trevis, T., & Korczyn, A. D. (1996). Changes in expression of lymphocyte amyloid precursor protein mRNA isoforms in normal aging and Alzheimer’s disease. Brain Research. Molecular Brain Research, 35, 260–268.PubMedGoogle Scholar
  24. Eckert, A., Forstl, H., Hartmann, H., Czech, C., Monning, U., Beyreuther, K., & Muller, W. E. (1995). The amplifying effect of beta-amyloid on cellular calcium signalling is reduced in Alzheimer’s disease. Neuroreport, 6, 1199–1202.PubMedGoogle Scholar
  25. Eckert, A., Oster, M., Zerfass, R., Hennerici, M., & Muller, W. E. (2001a). Elevated levels of fragmented DNA nucleosomes in native and activated lymphocytes indicate an enhanced sensitivity to apoptosis in sporadic Alzheimer’s disease. Specific differences to vascular dementia. Dementia and Geriatric Cognitive Disorders, 12, 98–105.PubMedGoogle Scholar
  26. Eckert, A., Schindowski, K., Leutner, S., Luckhaus, C., Touchet, N., Czech, C., & Muller, W. E. (2001b). Alzheimer’s disease-like alterations in peripheral cells from presenilin-1 transgenic mice. Neurobiology of Disease, 8, 331–342.PubMedGoogle Scholar
  27. Eisenbraun, M. D., Tamir, A., & Miller, R. A. (2000). Altered composition of the immunological synapse in an anergic, age-dependent memory T cell subset. Journal of Immunology, 164, 6105–6112.Google Scholar
  28. Engelhardt, B., & Ransohoff, R. M. (2005). The ins and outs of T-lymphocyte trafficking to the CNS: Anatomical sites and molecular mechanisms. Trends in Immunology, 26, 485–495.PubMedGoogle Scholar
  29. Esplugues, E., Sancho, D., Vega-Ramos, J., Martinez, C., Syrbe, U., Hamann, A., Engel, P., Sanchez-Madrid, F., & Lauzurica, P. (2003). Enhanced antitumor immunity in mice deficient in CD69. The Journal of Experimental Medicine, 197, 1093–1106.PubMedGoogle Scholar
  30. Fiala, M., Liu, Q. N., Sayre, J., Pop, V., Brahmandam, V., Graves, M. C., & Vinters, H. V. (2002). Cyclooxygenase-2-positive macrophages infiltrate the Alzheimer’s disease brain and damage the blood–brain barrier. European Journal of Clinical Investigation, 32, 360–371.PubMedGoogle Scholar
  31. Fields, P. E., Gajewski, T. F., & Fitch, F. W. (1996). Blocked Ras activation in anergic CD4+ T cells. Science, 271, 1276–1278.PubMedGoogle Scholar
  32. Ford, A. L., Foulcher, E., Lemckert, F. A., & Sedgwick, J. D. (1996). Microglia induce CD4 T lymphocyte final effector function and death. The Journal of Experimental Medicine, 184, 1737–1745.PubMedGoogle Scholar
  33. Frey, C., Bonert, A., Kratzsch, T., Rexroth, G., Rosch, W., Muller-Spahn, F., Maurer, K., Muller, W. E., & Eckert, A. (2006). Apolipoprotein E epsilon 4 is associated with an increased vulnerability to cell death in Alzheimer’s disease. Journal of Neural Transmission.Google Scholar
  34. Furlan, R., Brambilla, E., Sanvito, F., Roccatagliata, L., Olivieri, S., Bergami, A., Pluchino, S., Uccelli, A., Comi, G., & Martino, G. (2003). Vaccination with amyloid-beta peptide induces autoimmune encephalomyelitis in C57/BL6 mice. Brain, 126, 285–291.PubMedGoogle Scholar
  35. Galimberti, D., Schoonenboom, N., Scheltens, P., Fenoglio, C., Venturelli, E., Pijnenburg, Y. A., Bresolin, N., & Scarpini, E. (2006). Intrathecal chemokine levels in Alzheimer disease and frontotemporal lobar degeneration. Neurology, 66, 146–147.PubMedGoogle Scholar
  36. Gee, J. R., & Keller, J. N. (2005). Astrocytes: Regulation of brain homeostasis via apolipoprotein E. The International Journal of Biochemistry and Cell Biology, 37, 1145–1150.Google Scholar
  37. Geginat, J., Lanzavecchia, A., & Sallusto, F. (2003). Proliferation and differentiation potential of human CD8+ memory T-cell subsets in response to antigen or homeostatic cytokines. Blood, 101, 4260–4266.PubMedGoogle Scholar
  38. Gilman, S., Koller, M., Black, R. S., Jenkins, L., Griffith, S. G., Fox, N. C., Eisner, L., Kirby, L., Rovira, M. B., Forette, F., & Orgogozo, J. M. (2005). Clinical effects of Abeta immunization (AN1792) in patients with AD in an interrupted trial. Neurology, 64, 1553–1562.PubMedGoogle Scholar
  39. Giuliani, F., Goodyer, C. G., Antel, J. P., & Yong, V. W. (2003). Vulnerability of human neurons to T cell-mediated cytotoxicity. Journal of Immunology, 171, 368–379.Google Scholar
  40. Grossmann, A., Kukull, W. A., Jinneman, J. C., Bird, T. D., Villacres, E. C., Larson, E. B., & Rabinovitch, P. S. (1993). Intracellular calcium response is reduced in CD4+ lymphocytes in Alzheimer’s disease and in older persons with Down’s syndrome. Neurobiology of Aging, 14, 177–185.PubMedGoogle Scholar
  41. Guidi, L., Tricerri, A., Frasca, D., Vangeli, M., Errani, A. R., & Bartoloni, C. (1998). Psychoneuroimmunology and aging. Gerontology, 44, 247–261.PubMedGoogle Scholar
  42. Hanisch, U. K., Neuhaus, J., Quirion, R., & Kettenmann, H. (1996). Neurotoxicity induced by interleukin-2: Involvement of infiltrating immune cells. Synapse, 24, 104–114.PubMedGoogle Scholar
  43. Havenith, C. E., Askew, D., & Walker, W. S. (1998). Mouse resident microglia: Isolation and characterization of immunoregulatory properties with naive CD4+ and CD8+ T-cells. Glia, 22, 348–359.PubMedGoogle Scholar
  44. Hubert, P., Grenot, P., Autran, B., & Debre, P. (1997). Analysis by flow cytometry of tyrosine-phosphorylated proteins in activated T-cell subsets on whole blood samples. Cytometry, 29, 83–91.PubMedGoogle Scholar
  45. Iarlori, C., Gambi, D., Gambi, F., Lucci, I., Feliciani, C., Salvatore, M., & Reale, M. (2005). Expression and production of two selected beta-chemokines in peripheral blood mononuclear cells from patients with Alzheimer’s disease. Experimental Gerontology, 40, 605–611.PubMedGoogle Scholar
  46. Ibarreta, D., Parrilla, R., & Ayuso, M. S. (1997). Altered Ca2+ homeostasis in lymphoblasts from patients with late-onset Alzheimer disease. Alzheimer Disease and Associated Disorders, 11, 220–227.PubMedGoogle Scholar
  47. Ikeda, T., Yamamoto, K., Takahashi, K., Kaneyuki, H., & Yamada, M. (1991a). Interleukin-2 receptor in peripheral blood lymphocytes of Alzheimer’s disease patients. Acta Psychiatrica Scandinavica, 84, 262–265.PubMedGoogle Scholar
  48. Ikeda, T., Yamamoto, K., Takahashi, K., & Yamada, M. (1991b). Immune system-associated antigens on the surface of peripheral blood lymphocytes in patients with Alzheimer’s disease. Acta Psychiatrica Scandinavica, 83, 444–448.PubMedGoogle Scholar
  49. Itagaki, S., McGeer, P. L., & Akiyama, H. (1988). Presence of T-cytotoxic suppressor and leucocyte common antigen positive cells in Alzheimer’s disease brain tissue. Neuroscience Letters, 91, 259–264.PubMedGoogle Scholar
  50. Jang, I. K., & Gu, H. (2003). Negative regulation of TCR signaling and T-cell activation by selective protein degradation. Current Opinion in Immunology, 15, 315–320.PubMedGoogle Scholar
  51. Lassmann, H., & Ransohoff, R. M. (2004). The CD4-Th1 model for multiple sclerosis: A critical [correction of crucial] re-appraisal. Trends in Immunology, 25, 132–137.PubMedGoogle Scholar
  52. Ledoux, S., Rebai, N., Dagenais, A., Shaw, I. T., Nalbantoglu, J., Sekaly, R. P., & Cashman, N. R. (1993). Amyloid precursor protein in peripheral mononuclear cells is up-regulated with cell activation. Journal of Immunology, 150, 5566–5575.Google Scholar
  53. Lemere, C. A., Maron, R., Selkoe, D. J., & Weiner, H. L. (2001). Nasal vaccination with beta-amyloid peptide for the treatment of Alzheimer’s disease. DNA and Cell Biology, 20, 705–711.PubMedGoogle Scholar
  54. Lemere, C. A., Maron, R., Spooner, E. T., Grenfell, T. J., Mori, C., Desai, R., Hancock, W. W., Weiner, H. L., & Selkoe, D. J. (2000). Nasal A beta treatment induces anti-A beta antibody production and decreases cerebral amyloid burden in PD-APP mice. Annals of the New York Academy of Sciences, 920, 328–331.PubMedCrossRefGoogle Scholar
  55. Leutner, S., Czech, C., Schindowski, K., Touchet, N., Eckert, A., & Muller, W. E. (2000). Reduced antioxidant enzyme activity in brains of mice transgenic for human presenilin-1 with single or multiple mutations. Neuroscience Letters, 292, 87–90.PubMedGoogle Scholar
  56. Ligthart, G. J., Corberand, J. X., Fournier, C., Galanaud, P., Hijmans, W., Kennes, B., Muller-Hermelink, H. K., & Steinmann, G. G. (1984). Admission criteria for immunogerontological studies in man: The SENIEUR protocol. Mechanisms of Ageing and Development, 28, 47–55.PubMedGoogle Scholar
  57. Lombardi, V. R., Garcia, M., Rey, L., & Cacabelos, R. (1999). Characterization of cytokine production, screening of lymphocyte subset patterns and in vitro apoptosis in healthy and Alzheimer’s Disease (AD) individuals. Journal of Neuroimmunology, 97, 163–171.PubMedGoogle Scholar
  58. Maesaka, J. K., Palaia, T., Chowdhury, S. A., Shimamura, T., Fishbane, S., Reichman, W., Coyne, A., O’Rear, J. J., & El-Sabban, M. E. (1999). Partial characterization of apoptotic factor in Alzheimer plasma. The American Journal of Physiology, 276, F521–527.PubMedGoogle Scholar
  59. Masliah, E., Hansen, L., Adame, A., Crews, L., Bard, F., Lee, C., Seubert, P., Games, D., Kirby, L., & Schenk, D. (2005). Abeta vaccination effects on plaque pathology in the absence of encephalitis in Alzheimer disease. Neurology, 64, 129–131.PubMedGoogle Scholar
  60. Matyszak, M. K., Denis-Donini, S., Citterio, S., Longhi, R., Granucci, F., & Ricciardi-Castagnoli, P. (1999). Microglia induce myelin basic protein-specific T cell anergy or T cell activation, according to their state of activation. European Journal of Immunology, 29, 3063–3076.PubMedGoogle Scholar
  61. McGeer, P. L., Akiyama, H., Itagaki, S., & McGeer, E. G. (1989). Immune system response in Alzheimer’s disease. The Canadian Journal of Neurological Sciences, 16, 516–527.PubMedGoogle Scholar
  62. Mirshahidi, S., Ferris, L. C., & Sadegh-Nasseri, S. (2004). The magnitude of TCR engagement is a critical predictor of T cell anergy or activation. Journal of Immunology, 172, 5346–5355.Google Scholar
  63. Mirshahidi, S., Huang, C. T., & Sadegh-Nasseri, S. (2001). Anergy in peripheral memory CD4(+) T cells induced by low avidity engagement of T cell receptor. The Journal of Experimental Medicine, 194, 719–731.PubMedGoogle Scholar
  64. Monning, U., Konig, G., Banati, R. B., Mechler, H., Czech, C., Gehrmann, J., Schreiter-Gasser, U., Masters, C. L., & Beyreuther, K. (1992). Alzheimer beta A4-amyloid protein precursor in immunocompetent cells. The Journal of Biological Chemistry, 267, 23950–23956.PubMedGoogle Scholar
  65. Monsonego, A., Maron, R., Zota, V., Selkoe, D. J., & Weiner, H. L. (2001). Immune hyporesponsiveness to amyloid beta-peptide in amyloid precursor protein transgenic mice: Implications for the pathogenesis and treatment of Alzheimer’s disease. Proceedings of the National Academy of Sciences of the United States of America, 98, 10273–10278.PubMedGoogle Scholar
  66. Monsonego, A., Zota, V., Karni, A., Krieger, J. I., Bar-Or, A., Bitan, G., Budson, A. E., Sperling, R., Selkoe, D. J., & Weiner, H. L. (2003). Increased T cell reactivity to amyloid beta protein in older humans and patients with Alzheimer disease. The Journal of Clinical Investigation, 112, 415–422.PubMedGoogle Scholar
  67. Orgogozo, J. M., Gilman, S., Dartigues, J. F., Laurent, B., Puel, M., Kirby, L. C., Jouanny, P., Dubois, B., Eisner, L., Flitman, S., Michel, B. F., Boada, M., Frank, A., & Hock, C. (2003). Subacute meningoencephalitis in a subset of patients with AD after Abeta42 immunization. Neurology, 61, 46–54.PubMedGoogle Scholar
  68. Palotas, A., Kalman, J., Palotas, M., Juhasz, A., Janka, Z., & Penke, B. (2002). Beta-amyloid-induced increase in the resting intracellular calcium concentration gives support to tell Alzheimer lymphocytes from control ones. Brain Research Bulletin, 58, 203–205.PubMedGoogle Scholar
  69. Panossian, L. A., Porter, V. R., Valenzuela, H. F., Zhu, X., Reback, E., Masterman, D., Cummings, J. L., & Effros, R. B. (2003). Telomere shortening in T cells correlates with Alzheimer’s disease status. Neurobiology of Aging, 24, 77–84.PubMedGoogle Scholar
  70. Park, E., Alberti, J., Mehta, P., Dalton, A., Sersen, E., & Schuller-Levis, G. (2000). Partial impairment of immune functions in peripheral blood leukocytes from aged men with Down’s syndrome. Clinical Immunology, 95, 62–69.PubMedGoogle Scholar
  71. Pirttila, T., Mattinen, S., & Frey, H. (1992). The decrease of CD8-positive lymphocytes in Alzheimer’s disease. Journal of Neurological Sciences, 107, 160–165.Google Scholar
  72. Ratts, R. B., Karandikar, N. J., Hussain, R. Z., Choy, J., Northrop, S. C., Lovett-Racke, A. E., & Racke, M. K. (2006). Phenotypic characterization of autoreactive T cells in multiple sclerosis. Journal of Neuroimmunology, 178, 100–110.PubMedGoogle Scholar
  73. Robinson Agramonte, M., Dorta-Contreras, A. J., & Lorigados Pedre, L. (2001). Immune events in central nervous system of early and late onset Alzheimer’s disease patients. Revista de Neurologia, 32, 901–904.PubMedGoogle Scholar
  74. Rogers, J., & Mufson, E. J. (1990). Demonstrating immune-related antigens in Alzheimer’s disease brain tissue. Neurobiology of Aging, 11, 477–479.PubMedGoogle Scholar
  75. Rota, E., Bellone, G., Rocca, P., Bergamasco, B., Emanuelli, G., & Ferrero, P. (2006). Increased intrathecal TGF-beta1, but not IL-12, IFN-gamma and IL-10 levels in Alzheimer’s disease patients. Neurological Sciences, 27, 33–39.PubMedGoogle Scholar
  76. Rubin, B., Llobera, R., Gouaillard, C., Alcover, A., & Arnaud, J. (2000). Dissection of the role of CD3gamma chains in profound but reversible T-cell receptor down-regulation. Scandinavian Journal of Immunology, 52, 173–183.PubMedGoogle Scholar
  77. Sala, G., Galimberti, G., Canevari, C., Raggi, M. E., Isella, V., Facheris, M., Appollonio, I., & Ferrarese, C. (2003). Peripheral cytokine release in Alzheimer patients: Correlation with disease severity. Neurobiology of Aging, 24, 909–914.PubMedGoogle Scholar
  78. 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, 173–177.PubMedGoogle Scholar
  79. Schindowski, K., Frohlich, L., Maurer, K., Muller, W. E., & Eckert, A. (2002). Age-related impairment of human T lymphocytes’ activation: Specific differences between CD4(+) and CD8(+) subsets. Mechanisms of Ageing and Development, 123, 375–390.PubMedGoogle Scholar
  80. Schindowski, K., Kratzsch, T., Peters, J., Steiner, B., Leutner, S., Touchet, N., Maurer, K., Czech, C., Pradier, L., Frolich, L., Muller, W. E., & Eckert, A. (2003). Impact of aging: Sporadic, and genetic risk factors on vulnerability to apoptosis in Alzheimer’s disease. Neuromolecular Medicine, 4, 161–178.PubMedGoogle Scholar
  81. Schindowski, K., Leutner, S., Muller, W. E., & Eckert, A. (2000). Age-related changes of apoptotic cell death in human lymphocytes. Neurobiology of Aging, 21, 661–670.PubMedGoogle Scholar
  82. Schindowski, K., Peters, J., Gorriz, C., Schramm, U., Weinandi, T., Leutner, S., Maurer, K., Frölich, L., Muller, W. E., & Eckert, A. (2006). Apoptosis of CD4+ T and natural killer cells in Alzheimer’s disease. Pharmacopsychiatry, 39, 220–228.PubMedGoogle Scholar
  83. Schlunck, T., Schraut, W., Riethmuller, G., & Ziegler-Heitbrock, H. W. (1990). Inverse relationship of CA2+ mobilization and cell proliferation in CD8+ memory and virgin T cells. European Journal of Immunology, 20, 1957–1963.PubMedGoogle Scholar
  84. Schmid, I., Uittenbogaart, C. H., Keld, B., & Giorgi, J. V. (1994). A rapid method for measuring apoptosis and dual-color immunofluorescence by single laser flow cytometry. Journal of Immunological Methods, 170, 145–157.PubMedGoogle Scholar
  85. Schuessel, K., Schafer, S., Bayer, T. A., Czech, C., Pradier, L., Muller-Spahn, F., Muller, W. E., & Eckert, A. (2005). Impaired Cu/Zn-SOD activity contributes to increased oxidative damage in APP transgenic mice. Neurobiology of Disease, 18, 89–99.PubMedGoogle Scholar
  86. Seabrook, T. J., Thomas, K., Jiang, L., Bloom, J., Spooner, E., Maier, M., Bitan, G., & Lemere, C. A. (2007). Dendrimeric Abeta1-15 is an effective immunogen in wildtype and APP-tg mice. Neurobiology of Aging, 28, 813–823.PubMedGoogle Scholar
  87. Sedgwick, J. D., Mossner, R., Schwender, S., & ter Meulen, V. (1991). Major histocompatibility complex-expressing nonhematopoietic astroglial cells prime only CD8+ T lymphocytes: Astroglial cells as perpetuators but not initiators of CD4+ T cell responses in the central nervous system. Journal of Experimental Medicine, 173, 1235–1246.PubMedGoogle Scholar
  88. Shalit, F., Sredni, B., Brodie, C., Kott, E., & Huberman, M. (1995). T lymphocyte subpopulations and activation markers correlate with severity of Alzheimer’s disease. Clinical Immunology and Immunopathology, 75, 246–250.PubMedGoogle Scholar
  89. Singh, V. K. (1990). Neuroimmune axis as a basis of therapy in Alzheimer’s disease. Progress in Drug Research, 34, 383–393.PubMedGoogle Scholar
  90. Stieler, J. T., Lederer, C., Bruckner, M. K., Wolf, H., Holzer, M., Gertz, H. J., & Arendt, T. (2001). Impairment of mitogenic activation of peripheral blood lymphocytes in Alzheimer’s disease. Neuroreport, 12, 3969–3972.PubMedGoogle Scholar
  91. Tan, J., Town, T., Abdullah, L., Wu, Y., Placzek, A., Small, B., Kroeger, J., Crawford, F., Richards, D., & Mullan, M. (2002). CD45 isoform alteration in CD4+ T cells as a potential diagnostic marker of Alzheimer’s disease. Journal of Neuroimmunology, 132, 164–172.PubMedGoogle Scholar
  92. Tanchot, C., Rosado, M. M., Agenes, F., Freitas, A. A., & Rocha, B. (1997). Lymphocyte homeostasis. Seminars in Immunology, 9, 331–337.PubMedGoogle Scholar
  93. 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. Journal of Neuroimmunology, 124, 83–92.PubMedGoogle Scholar
  94. Torres, P. S., Alcover, A., Zapata, D. A., Arnaud, J., Pacheco, A., Martin-Fernandez, J. M., Villasevil, E. M., Sanal, O., & Regueiro, J. R. (2003). TCR dynamics in human mature T lymphocytes lacking CD3 gamma. Journal of Immunology, 170, 5947–5955.Google Scholar
  95. Town, T., Tan, J., Flavell, R. A., & Mullan, M. (2005). T-cells in Alzheimer’s disease. Neuromolecular Medicine, 7, 255–264.PubMedGoogle Scholar
  96. Town, T., Tan, J., Sansone, N., Obregon, D., Klein, T., & Mullan, M. (2001). Characterization of murine immunoglobulin G antibodies against human amyloid-beta1-42. Neuroscience Letters, 307, 101–104.PubMedGoogle Scholar
  97. Town, T., Vendrame, M., Patel, A., Poetter, D., DelleDonne, A., Mori, T., Smeed, R., Crawford, F., Klein, T., Tan, J., & Mullan, M. (2002). Reduced Th1 and enhanced Th2 immunity after immunization with Alzheimer’s beta-amyloid(1-42). Journal of Neuroimmunology, 132, 49–59.PubMedGoogle Scholar
  98. Trieb, K., Ransmayr, G., Sgonc, R., Lassmann, H., & Grubeck-Loebenstein, B. (1996). APP peptides stimulate lymphocyte proliferation in normals, but not in patients with Alzheimer’s disease. Neurobiology of Aging, 17, 541–547.PubMedGoogle Scholar
  99. Valitutti, S., Muller, S., Cella, M., Padovan, E., & Lanzavecchia, A. (1995). Serial triggering of many T-cell receptors by a few peptide-MHC complexes. Nature, 375, 148–151.PubMedGoogle Scholar
  100. Vingtdeux, V., Hamdane, M., Gompel, M., Begard, S., Drobecq, H., Ghestem, A., Grosjean, M. E., Kostanjevecki, V., Grognet, P., Vanmechelen, E., Buee, L., Delacourte, A., & Sergeant, N. (2005). Phosphorylation of amyloid precursor carboxy-terminal fragments enhances their processing by a gamma-secretase-dependent mechanism. Neurobiology of Disease, 20, 625–637.PubMedGoogle Scholar
  101. Weishaupt, A., Jander, S., Bruck, W., Kuhlmann, T., Stienekemeier, M., Hartung, T., Toyka, K. V., Stoll, G., & Gold, R. (2000). Molecular mechanisms of high-dose antigen therapy in experimental autoimmune encephalomyelitis: Rapid induction of Th1-type cytokines and inducible nitric oxide synthase. Journal of Immunology, 165, 7157–7163.Google Scholar
  102. Wenham, P. R., Price, W. H., & Blandell, G. (1991). Apolipoprotein E genotyping by one-stage PCR. Lancet, 337, 1158–1159.PubMedGoogle Scholar
  103. Zhang, J., Kong, Q., Zhang, Z., Ge, P., Ba, D., & He, W. (2003). Telomere dysfunction of lymphocytes in patients with Alzheimer disease. Cognitive and Behavirol Neurology, 16, 170–176.Google Scholar

Copyright information

© Humana Press Inc. 2007

Authors and Affiliations

  • Katharina Schindowski
    • 1
    • 2
    Email author
  • Anne Eckert
    • 1
    • 3
  • Jürgen Peters
    • 4
  • Corinna Gorriz
    • 4
  • Uta Schramm
    • 4
  • Thomas Weinandi
    • 4
  • Konrad Maurer
    • 4
  • Lutz Frölich
    • 4
    • 5
  • Walter E. Müller
    • 1
  1. 1.Institute of Pharmacology, Biocenter building N260Johann Wolfgang-Goethe-UniversityFrankfurt am MainGermany
  2. 2.INSERM, U837, Faculté de Médecine, Institut de Médecine Prédictive et Recherche ThérapeutiqueUniversité Lille 2Lille CedexFrance
  3. 3.Psychiatric University Clinic BaselBaselSwitzerland
  4. 4.Department of Psychiatry and Psychotherapy IJohann Wolfgang-Goethe-UniversityFrankfurt am MainGermany
  5. 5.Central Institute for Mental Health, Department for Gerontopsychiatry, Faculty for clinical medicineUniversity HeidelbergMannheimGermany

Personalised recommendations