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

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 APP_751SL × PS1_M146L 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
• 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
• 3 Avula CP, Fernandes G. Inhibition of H₂O₂-induced apoptosis of lymphocytes by calorie restriction during aging.  Microsc Res Tech. 2002;  59 282-292
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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)
• 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
• 17 Guidi L, Tricerri A, Frasca D, Vangeli M, Errani AR, Bartoloni C. Psychoneuroimmunology and aging.  Gerontology. 1998;  44 247-261
• 18 Gupta S. Molecular and biochemical pathways of apoptosis in lymphocytes from aged humans.  Vaccine. 2000;  18 1596-1601
• 19 Hanisch UK, Neuhaus J, Quirion R, Kettenmann H. Neurotoxicity induced by interleukin-2: involvement of infiltrating immune cells.  Synapse. 1996;  24 104-114
• 20 Hickey WF. Basic principles of immunological surveillance of the normal central nervous system.  Glia. 2001;  36 118-124
• 21 Hildeman DA, Mitchell T, Kappler J, Marrack P. T cell apoptosis and reactive oxygen species.  J Clin Invest. 2003;  111 575-581
• 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
• 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
• 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
• 25 Laskowitz DT, Goel S, Bennett ER, Matthew WD. Apolipoprotein E suppresses glial cell secretion of TNF alpha.  J Neuroimmunol. 1997;  76 70-74
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 33 McGavern DB. The role of bystander T cells in CNS pathology and pathogen clearance.  Crit Rev Immunol. 2005;  25 289-303
• 34 McGeer PL, McGeer EG. Inflammation and the degenerative diseases of aging.  Ann N Y Acad Sci. 2004;  1035 104-116
• 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
• 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
• 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
• 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
• 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
• 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
• 41 Pirttila T, Mattinen S, Frey H. The decrease of CD8-positive lymphocytes in Alzheimer's disease.  J Neurol Sci. 1992;  107 160-165
• 42 Rogers SL, Coe CL, Karaszewski JW. Immune consequences of stroke and cerebral palsy in adults.  J Neuroimmunol. 1998;  91 113-120
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 52 Singh VK. Neuroimmune axis as a basis of therapy in Alzheimer's disease.  Prog Drug Res. 1990;  34 383-393
• 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
• 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
• 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
• 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
• 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
• 58 Wenham PR, Price WH, Blandell G. Apolipoprotein E genotyping by one-stage PCR.  Lancet. 1991;  337 1158-1159
• 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

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