PDF herunterladen
Pharmacopsychiatry 2006; 39(6): 220-228
DOI: 10.1055/s-2006-954591
Original Paper

© Georg Thieme Verlag KG Stuttgart · New York

Apoptosis of CD4+ T and Natural Killer Cells in Alzheimer's Disease

K. Schindowski 1 , 2 , J. Peters 3 , C. Gorriz 3 , 6 , U. Schramm 3 , T. Weinandi 3 , S. Leutner 1 , K. Maurer 3 , L. Frölich 3 , 5 , W. E. Müller 1 , A. Eckert 1 , 4
  • 1Institute of Pharmacology, Biocenter, Johann Wolfgang-Goethe-University, Frankfurt, Germany
  • 2Present address: INSERM U815, Université Lille 2, Faculté de Médecine, Institut de Médecine Prédictive et Recherche Thérapeutique, Lille Cedex, France
  • 3Department of Psychiatry and Psychotherapy I, Johann Wolfgang-Goethe-University, Frankfurt, Germany
  • 4Present address: Psychiatric University Clinic Basel, Basel, Switzerland
  • 5Central Institute for Mental Health, Monnhein, Germany
  • 6Department of Psychiatry, University Mainz, Mainz, Germany
Weitere Informationen

Publikationsverlauf

Received 25. 5. 2006 Revised 18. 7. 2006

Accepted 25. 7. 2006

Publikationsdatum:
23. November 2006 (online)

Auch verfügbar auf
    Lizenzen und Reprints

Background: Immunotherapy appears to be a potent treatment against Alzheimer's disease (AD), but the mechanisms underlying neural-immune interaction are still not known. Methods: Here, we determined cell death and distribution of lymphocyte subsets of peripheral blood mononuclear cells (PBMC) in AD and aging, e.g. T (CD4+CD3+, CD8+CD3+), B (CD19+) and NK (CD16++CD56+) cells. Results: Increased apoptosis was found in CD4+ T and NK cells in AD, while in aging all subsets were affected. The expression of anti-apoptotic Bcl2 correlated with observed cell death in T-helper and B cells irrespective of dementia. The levels of Bcl2 in T-cells were significantly increased in mild AD. Apoptosis and Bcl2 levels were also elevated in the APP751SL × PS1M146L transgenic mouse model. Conclusion: The mechanisms triggering apoptosis and activation of lymphocytes in AD appear therefore to be different than those in immunosenescence and possibly bear an important biomarker to monitor immunotherapy in AD.

References

  • 1 Aggarwal S, Gupta S. Increased apoptosis of T cell subsets in aging humans: altered expression of Fas (CD95), Fas ligand, Bcl-2, and Bax.  J Immunol. 1998;  160 1627-1637
    PubMedSuche in Google Scholar
  • 2 Araga S, Kagimoto H, Funamoto K, Takahashi K. Reduced natural killer cell activity in patients with dementia of the Alzheimer type.  Acta Neurol Scand. 1991;  84 259-263
    PubMedSuche in Google Scholar
  • 3 Avula CP, Fernandes G. Inhibition of H2O2-induced apoptosis of lymphocytes by calorie restriction during aging.  Microsc Res Tech. 2002;  59 282-292
    CrossrefPubMedSuche in Google Scholar
  • 4 Baba Y, Kuroiwa A, Uitti RJ, Wszolek ZK, Yamada T. Alterations of T-lymphocyte populations in Parkinson disease.  Parkinsonism Relat Disord. 2005;  11 493-498
    CrossrefPubMedSuche in Google Scholar
  • 5 Baumann S, Krueger A, Kirchhoff S, Krammer PH. Regulation of T cell apoptosis during the immune response.  Curr Mol Med. 2002;  2 257-272
    CrossrefPubMedSuche in Google Scholar
  • 6 Blanchard V, Moussaoui S, Czech C, Touchet N, Bonici B, Planche M, Canton T, Jedidi I, Gohin M, Wirths O, Bayer TA, Langui D, Duyckaerts C, Tremp G, Pradier L. Time sequence of maturation of dystrophic neurites associated with Abeta deposits in APP/PS1 transgenic mice.  Exp Neurol. 2003;  184 247-263
    CrossrefPubMedSuche in Google Scholar
  • 7 Bullido MJ, Munoz-Fernandez MA, Recuero M, Fresno M, Valdivieso F. Alzheimer's amyloid precursor protein is expressed on the surface of hematopoietic cells upon activation.  Biochim Biophys Acta. 1996;  1313 54-62
    PubMedSuche in Google Scholar
  • 8 Carson MJ, Sutcliffe JG. Balancing function vs. self defense: the CNS as an active regulator of immune responses.  J Neurosci Res. 1999;  55 1-8
    CrossrefPubMedSuche in Google Scholar
  • 9 Colton CA, Brown CM, Cook D, Needham LK, Xu Q, Czapiga M, Saunders AM, Schmechel DE, Rasheed K, Vitek MP. APOE and the regulation of microglial nitric oxide production: a link between genetic risk and oxidative stress.  Neurobiol Aging. 2002;  23 777-785
    CrossrefPubMedSuche in Google Scholar
  • 10 Czech C, Delaere P, Macq AF, Reibaud M, Dreisler S, Touchet N, Schombert B, Mazadier M, Mercken L, Theisen M, Pradier L, Octave JN, Beyreuther K, Tremp G. Proteolytical processing of mutated human amyloid precursor protein in transgenic mice.  Brain Res Mol Brain Res. 1997;  47 108-116
    PubMedSuche in Google Scholar
  • 11 Ebstein RP, Nemanov L, Lubarski G, Dano M, Trevis T, Korczyn AD. Changes in expression of lymphocyte amyloid precursor protein mRNA isoforms in normal aging and Alzheimer's disease.  Brain Res Mol Brain Res. 1996;  35 260-268
    PubMedSuche in Google Scholar
  • 12 Eckert A, Cotman CW, Zerfass R, Hennerici M, Muller WE. Enhanced vulnerability to apoptotic cell death in sporadic Alzheimer's disease.  Neuroreport. 1998;  9 2443-2446
    PubMedSuche in Google Scholar
  • 13 Eckert A, Oster M, Zerfass R, Hennerici M, Muller WE. 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.  Dement Geriatr Cogn Disord. 2001;  12 98-105
    CrossrefPubMedSuche in Google Scholar
  • 14 Effros RB, Dagarag M, Spaulding C, Man J. The role of CD8+T-cell replicative senescence in human aging.  Immunol Rev. 2005;  205 147-157
    CrossrefPubMedSuche in Google Scholar
  • 15 Frey C, Bonert A, Kratzsch T, Rexroth G, Rösch W, Müller-Spahn F, Maurer K, Müller WE, Eckert A. Apolipoprotein E epsilon 4 is associated with an increased vulnerability to cell death in Alzheimer's disease.  J Neural Trans. 2006;  , (in press)
    PubMedSuche in Google Scholar
  • 16 Fukuyama R, Murakawa Y, Rapoport SI. Induction of gene expression of amyloid precursor protein (APP) in activated human lymphoblastoid cells and lymphocytes.  Mol Chem Neuropathol. 1994;  23 93-101
    PubMedSuche in Google Scholar
  • 17 Guidi L, Tricerri A, Frasca D, Vangeli M, Errani AR, Bartoloni C. Psychoneuroimmunology and aging.  Gerontology. 1998;  44 247-261
    CrossrefPubMedSuche in Google Scholar
  • 18 Gupta S. Molecular and biochemical pathways of apoptosis in lymphocytes from aged humans.  Vaccine. 2000;  18 1596-1601
    CrossrefPubMedSuche in Google Scholar
  • 19 Hanisch UK, Neuhaus J, Quirion R, Kettenmann H. Neurotoxicity induced by interleukin-2: involvement of infiltrating immune cells.  Synapse. 1996;  24 104-114
    CrossrefPubMedSuche in Google Scholar
  • 20 Hickey WF. Basic principles of immunological surveillance of the normal central nervous system.  Glia. 2001;  36 118-124
    CrossrefPubMedSuche in Google Scholar
  • 21 Hildeman DA, Mitchell T, Kappler J, Marrack P. T cell apoptosis and reactive oxygen species.  J Clin Invest. 2003;  111 575-581
    CrossrefPubMedSuche in Google Scholar
  • 22 Ibarreta D, Parrilla R, Ayuso MS. Altered Ca2+ homeostasis in lymphoblasts from patients with late-onset Alzheimer disease.  Alzheimer Dis Assoc Disord. 1997;  11 220-227
    PubMedSuche in Google Scholar
  • 23 Jakab K, Novak Z, Engelhardt JI, Kemeny L, Kalman J, Vecsei L, Rasko I. UVB irradiation-induced apoptosis increased in lymphocytes of Huntington's disease patients.  Neuroreport. 2001;  12 1653-1656
    PubMedSuche in Google Scholar
  • 24 Kleine TO, Benes L. Immune surveillance of the human central nervous system (CNS): different migration pathways of immune cells through the blood-brain barrier and blood-cerebrospinal fluid barrier in healthy persons.  Cytometry A. 2006;  69 147-151
    PubMedSuche in Google Scholar
  • 25 Laskowitz DT, Goel S, Bennett ER, Matthew WD. Apolipoprotein E suppresses glial cell secretion of TNF alpha.  J Neuroimmunol. 1997;  76 70-74
    CrossrefPubMedSuche in Google Scholar
  • 26 Ledoux S, Bergeron C, Nalbantoglu J, Gauthier S, Cashman NR. Polymerase chain reaction quantification of lymphoid amyloid precursor protein mRNAs in Alzheimer's disease and Down's syndrome.  Neurosci Lett. 1995;  193 137-139
    CrossrefPubMedSuche in Google Scholar
  • 27 Ledoux S, Rebai N, Dagenais A, Shaw IT, Nalbantoglu J, Sekaly RP, Cashman NR. Amyloid precursor protein in peripheral mononuclear cells is up-regulated with cell activation.  J Immunol. 1993;  150 5566-5575
    PubMedSuche in Google Scholar
  • 28 Leutner S, Schindowski K, Frölich I, Maurer K, Kratzsch T, Eckert A, Müller WE. Enhanced ROS-Generation in Lymphocytes from Alzheimer's Patients.  Pharmacopsychiatry. 2005;  38 312-315
    Thieme ConnectPubMedSuche in Google Scholar
  • 29 Ligthart GJ, Corberand JX, Fournier C, Galanaud P, Hijmans W, Kennes B, Muller-Hermelink HK, Steinmann GG. Admission criteria for immunogerontological studies in man: the SENIEUR protocol.  Mech Ageing Dev. 1984;  28 47-55
    CrossrefPubMedSuche in Google Scholar
  • 30 Lombardi VR, Garcia M, Cacabelow R. APOE-induced microglial activation: an in vitro assay to screen sera from Alzheimer's disease patients and novel therapeutic compounds.  Methods Find Exp Clin Pharmacol. 1998;  20 377-386
    CrossrefPubMedSuche in Google Scholar
  • 31 Lombardi VR, Garcia M, Rey L, Cacabelos R. Characterization of cytokine production, screening of lymphocyte subset patterns and in vitro apoptosis in healthy and Alzheimer's Disease (AD) individuals.  J Neuroimmunol. 1999;  97 163-171
    CrossrefPubMedSuche in Google Scholar
  • 32 Masera RG, Prolo P, Sartori ML, Staurenghi A, Griot G, Ravizza L, Dovio A, Chiappelli F, Angeli A. Mental deterioration correlates with response of natural killer (NK) cell activity to physiological modifiers in patients with short history of Alzheimer's disease.  Psychoneuroendocrinology. 2002;  27 447-461
    CrossrefPubMedSuche in Google Scholar
  • 33 McGavern DB. The role of bystander T cells in CNS pathology and pathogen clearance.  Crit Rev Immunol. 2005;  25 289-303
    CrossrefPubMedSuche in Google Scholar
  • 34 McGeer PL, McGeer EG. Inflammation and the degenerative diseases of aging.  Ann N Y Acad Sci. 2004;  1035 104-116
    CrossrefPubMedSuche in Google Scholar
  • 35 Monning U, Konig G, Prior R, Mechler H, Schreiter-Gasser U, Masters CL, Beyreuther K. Synthesis and secretion of Alzheimer amyloid beta A4 precursor protein by stimulated human peripheral blood leucocytes.  FEBS Lett. 1990;  277 261-266
    CrossrefPubMedSuche in Google Scholar
  • 36 Monsonego A, Zota V, Karni A, Krieger JI, Bar-Or A, Bitan G, Budson AE, Sperling R, Selkoe DJ, Weiner HL. Increased T cell reactivity to amyloid beta protein in older humans and patients with Alzheimer disease.  J Clin Invest. 2003;  112 415-422
    CrossrefPubMedSuche in Google Scholar
  • 37 Nicoletti I, Migliorati G, Pagliacci MC, Grignani F, Riccardi C. A rapid and simple method for measuring thymocyte apoptosis by propidium iodide staining and flow cytometry.  J Immunol Methods. 1991;  139 271-279
    CrossrefPubMedSuche in Google Scholar
  • 38 Park E, Alberti J, Mehta P, Dalton A, Sersen E, Schuller-Levis G. Partial impairment of immune functions in peripheral blood leukocytes from aged men with Down's syndrome.  Clin Immunol. 2000;  95 62-69
    CrossrefPubMedSuche in Google Scholar
  • 39 Perry VH. The influence of systemic inflammation on inflammation in the brain: implications for chronic neurodegenerative disease.  Brain Behav Immun. 2004;  18 407-413
    CrossrefPubMedSuche in Google Scholar
  • 40 Pfeifer M, Boncristiano S, Bondolfi L, Stalder A, Deller T, Staufenbiel M, Mathews PM, Jucker M. Cerebral hemorrhage after passive anti-Abeta immunotherapy.  Science. 2002;  298 1379
    CrossrefPubMedSuche in Google Scholar
  • 41 Pirttila T, Mattinen S, Frey H. The decrease of CD8-positive lymphocytes in Alzheimer's disease.  J Neurol Sci. 1992;  107 160-165
    CrossrefPubMedSuche in Google Scholar
  • 42 Rogers SL, Coe CL, Karaszewski JW. Immune consequences of stroke and cerebral palsy in adults.  J Neuroimmunol. 1998;  91 113-120
    CrossrefPubMedSuche in Google Scholar
  • 43 Rostaing L, Puyoo O, Tkaczuk J, Peres C, Rouzaud A, Cisterne JM, de Preval C, Ohayon E, Durand D, Abbal M. Differences in Type 1 and Type 2 intracytoplasmic cytokines, detected by flow cytometry, according to immunosuppression (cyclosporine A vs. tacrolimus) in stable renal allograft recipients.  Clin Transplant. 1999;  13 400-409
    CrossrefPubMedSuche in Google Scholar
  • 44 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-beta attenuates Alzheimer-disease-like pathology in the PDAPP mouse.  Nature. 1999;  400 173-177
    CrossrefPubMedSuche in Google Scholar
  • 45 Schindowski K, Leutner S, Muller WE, Eckert A. Age-related changes of apoptotic cell death in human lymphocytes.  Neurobiol Aging. 2000;  21 661-670
    CrossrefPubMedSuche in Google Scholar
  • 46 Schindowski K, Frohlich L, Maurer K, Muller WE, Eckert A. Age-related impairment of human T lymphocytes' activation: specific differences between CD4(+) and CD8(+) subsets.  Mech Ageing Dev. 2002;  123 375-390
    CrossrefPubMedSuche in Google Scholar
  • 47 Schindowski K, Kratzsch T, Peters J, Steiner B, Leutner S, Touchet N, Maurer K, Czech C, Pradier L, Frohlich L, Muller WE, Eckert A. Impact of aging: sporadic, and genetic risk factors on vulnerability to apoptosis in Alzheimer's disease.  Neuromolecular Med. 2003;  4 161-178
    CrossrefPubMedSuche in Google Scholar
  • 48 Schmid I, Uittenbogaart CH, Keld B, Giorgi JV. A rapid method for measuring apoptosis and dual-color immunofluorescence by single laser flow cytometry.  J Immunol Methods. 1994;  170 145-157
    CrossrefPubMedSuche in Google Scholar
  • 49 Schuessel K, Schafer S, Bayer TA, Czech C, Pradier L, Muller-Spahn F, Muller WE, Eckert A. Impaired Cu/Zn-SOD activity contributes to increased oxidative damage in APP transgenic mice.  Neurobiol Dis. 2005;  18 89-99
    CrossrefPubMedSuche in Google Scholar
  • 50 Shalit F, Sredni B, Brodie C, Kott E, Huberman M. T lymphocyte subpopulations and activation markers correlate with severity of Alzheimer's disease.  Clin Immunol Immunopathol. 1995;  75 246-250
    CrossrefPubMedSuche in Google Scholar
  • 51 Shearer WT, Rosenblatt HM, Gelman RS, Oyomopito R, Plaeger S, Stiehm ER, Wara DW, Douglas SD, Luzuriaga K, McFarland EJ, Yogev R, Rathore MH, Levy W, Graham BL, Spector SA. Lymphocyte subsets in healthy children from birth through 18 years of age: the Pediatric AIDS Clinical Trials Group P1009 study.  J Allergy Clin Immunol. 2003;  112 973-980
    CrossrefPubMedSuche in Google Scholar
  • 52 Singh VK. Neuroimmune axis as a basis of therapy in Alzheimer's disease.  Prog Drug Res. 1990;  34 383-393
    PubMedSuche in Google Scholar
  • 53 Solerte SB, Cravello L, Ferrari E, Fioravanti M. Overproduction of IFN-gamma and TNF-alpha from natural killer (NK) cells is associated with abnormal NK reactivity and cognitive derangement in Alzheimer's disease.  Ann N Y Acad Sci. 2000;  917 331-340
    PubMedSuche in Google Scholar
  • 54 Solerte SB, Fioravanti M, Pascale A, Ferrari E, Govoni S, Battaini F. Increased natural killer cell cytotoxicity in Alzheimer's disease may involve protein kinase C dysregulation.  Neurobiol Aging. 1998;  19 191-199
    CrossrefPubMedSuche in Google Scholar
  • 55 Suh YH, Chong YH, Kim SH, Choi W, Min K, Jeong SJ, Fraser SP, Djamgoz MB. Molecular physiology, biochemistry, and pharmacology of Alzheimer's amyloid precursor protein (APP).  Ann N Y Acad Sci. 1996;  786 169-183
    PubMedSuche in Google Scholar
  • 56 Tan J, Town T, Abdullah L, Wu Y, Placzek A, Small B, Kroeger J, Crawford F, Richards D, Mullan M. CD45 isoform alteration in CD4+ T cells as a potential diagnostic marker of Alzheimer's disease.  J Neuroimmunol. 2002;  132 164-172
    CrossrefPubMedSuche in Google Scholar
  • 57 Togo T, Akiyama H, Iseki E, Kondo H, Ikeda K, Kato M, Oda T, Tsuchiya K, Kosaka K. Occurrence of T cells in the brain of Alzheimer's disease and other neurological diseases.  J Neuroimmunol. 2002;  124 83-92
    CrossrefPubMedSuche in Google Scholar
  • 58 Wenham PR, Price WH, Blandell G. Apolipoprotein E genotyping by one-stage PCR.  Lancet. 1991;  337 1158-1159
    PubMedSuche in Google Scholar
  • 59 Zhang X, Fujii H, Kishimoto H, LeRoy E, Surh CD, Sprent J. Aging leads to disturbed homeostasis of memory phenotype CD8(+) cells.  J Exp Med. 2002;  195 283-293
    CrossrefPubMedSuche in Google Scholar

Correspondence

Katharina Schindowski

INSERM U815

1 Place de Verdun

59045 Lille Cedex

France

Telefon: +33/320/62 20 74

Fax: +33/320/62 20 79

eMail: Katharina.Schindowski@lille.inserm.fr