Aktuelle Neurologie 2001; 28(1): 17-25
DOI: 10.1055/s-2001-10724
ÜBERSICHT
Übersicht
© Georg Thieme Verlag Stuttgart · New York

Apoptotischer Zelltod bei neuroinflammatorischen und neurodegenerativen Erkrankungen

R. Gold1 , Christine Stadelmann2 , W. Brück2 , H. Lassmann3
  • 1Klinische Forschungsgruppe für multiple Sklerose und Neuroimmunologie, Neurologische Universitätsklinik Würzburg
  • 2Institut für Neuropathologie, Charité, Berlin
  • 3Institut für Hirnforschung der Universität Wien, Abteilung für Neuroimmunologie
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Publikationsverlauf

Publikationsdatum:
31. Dezember 2001 (online)

Zusammenfassung

Der apoptotische Zelltod ist im letzten Jahrzehnt zunehmend ins Interesse bei verschiedenen neurobiologischen und neuroimmunologischen Fragestellungen gerückt. Obwohl Apoptose einen primär morphologisch definierten Begriff darstellt, ist er mit einer Reihe molekular-definierter Vorgänge verbunden und hat vielfältige funktionelle Bedeutung. Wir besprechen im Folgenden die verfügbaren Nachweismethoden für Apoptose, das Auftreten von T-Zellapoptose bei neuroimmunologischen Erkrankungen sowie den apoptotischen neuronalen Zelltod in Neurodegeneration und Ischämie. Die therapeutische Nutzung durch Induktion von Apoptose bei entzündlichen Erkrankungen bzw. deren Verhinderung bei degenerativen Prozessen wird zukünftig nur in enger Kooperation verschiedener Forschungsrichtungen gelingen.

Apoptotic Cell Death in Neuroinflammatory and Neurodegenerative Diseases

Apoptotic cell death has gained increased importance in neurobiology and neuroimmunology. Although apoptosis is per se defined by morphology, it is intimately linked to a series of molecular events and has a wide array of functional implications. Here, we summarise the available detection assays for apoptosis and the current state of research concerning T cell apoptosis in neuroimmunology and apoptotic neuronal cell death in neurodegeneration and ischemia. There is a clear therapeutic potential by induction of apoptosis in inflammatory diseases. Furthermore, protection from apoptotic cell death may be a promising tool in neurodegenerative and ischemic processes. In the future, this will necessitate a close cooperation between different fields of biology research.

Literatur

  • 1 Kerr J FR, Wyllie A H, Currie A R. Apoptosis: a basic biological phenomenon with wide ranging implications in tissue kinetics.  Br J Cancer. 1972;  26 239-257
  • 2 Gold R, Hartung H P, Lassmann H. T-cell apoptosis in autoimmune diseases: termination of inflammation in the nervous system and other sites with specialized immune-defense mechanisms.  Trends Neurosci. 1997;  20 399-404
  • 3 Wyllie A H. Glucocorticoid-induced thymocyte apoptosis is associated with endogenous endonuclease activation.  Nature. 1980;  284 555-556
  • 4 Cohen J J, Duke R C, Fadok V A, Sellins K S. Apoptosis and programmed cell death in immunity.  Annu Rev Immunol. 1992;  10 267-293
  • 5 Bursch W, Paffe S, Putz B. et al . Determination of the length of the histological stages of apoptosis in normal liver and in altered hepatic foci of rats.  Carcinogenesis. 1990;  11 847-853
  • 6 Schulze-Osthoff K, Walczak H, Dröge W, Krammer P H. Cell nucleus and DNA fragmentation are not required for apoptosis.  J Cell Biol. 1994;  127 15-20
  • 7 Nguyen K B, Pender M P. Phagocytosis of apoptotic lymphocytes by oligodendrocytes in experimental autoimmune encephalomyelitis.  Acta Neuropathol (Berl). 1998;  95 40-46
  • 8 Chan A, Magnus T, Gold R. Phagocytosis of apoptotic inflammatory cells by microglia and modulation by different cytokines: a mechanism for removal of apoptotic cells in the inflamed nervous system. Glia 2000 in press
  • 9 Ren Y, Savill J. Apoptosis: The importance of being eaten.  Cell Death Differ. 1998;  5 563-568
  • 10 Gavrieli Y, Sherman Y, Ben Sasson S A. Identification of programmed cell death in situ via specific labeling of nuclear DNA fragmentation.  J Cell Biol. 1992;  119 493-501
  • 11 Gold R, Schmied M, Giegerich G. et al . Differentiation between cellular apoptosis and necrosis by the combined use of in situ tailing and nick translation techniques.  Lab Invest. 1994;  71 219-225
  • 12 Nicholson D W. Caspase structure, proteolytic substrates, and function during apoptotic cell death.  Cell Death Differ. 1999;  6 1028-1042
  • 13 Samali A, Zhivotovsky B, Jones D. et al . Apoptosis: Cell death defined by caspase activation.  Cell Death Differ. 1999;  6 495-496
  • 14 Vermes I, Haanen C, Steffens-Nakken H, Reutelingsperger C. A novel assay for apoptosis. Flow cytometric detection of phosphatidylserine expression on early apoptotic cells using fluorescein labelled annexin V.  J Immunol Meth. 1995;  184 39-51
  • 15 Kroemer G, Dallaporta B, Resche-Rigon M. The mitochondrial death/life regulator in apoptosis and necrosis.  Annu Rev Physiol. 1998;  60 619-642
  • 16 Granville D J, Carthy C M, Hunt D WC, McManus B M. Apoptosis: Molecular aspects of cell death and disease.  Lab Invest. 1998;  78 893-913
  • 17 Stadelmann C, Lassmann H. Detection of apoptosis in tissue sections.  Cell Tissue Res. 2000;  301 19-31
  • 18 Tomei L D, Shapiro J P, Cope F O. Apoptosis in C3H/10T1/2 mouse embryonic cells: evidence for internucleosomal DNA modification in the absence of double-strand cleavage.  Proc Natl Acad Sci. 1993;  90 853-857
  • 19 Oberhammer F, Wilson J W, Dive C. et al . Apoptotic death in epithelial cells: cleavage of DNA to 300 and/or 50 kb fragments prior to or in the absence of internucleosomal fragmentation.  EMBO J. 1993;  12 3679-3684
  • 20 Virchow R. Die Cellularpathologie in ihrer Begründung auf physiologische und pathologische Gewebelehre. Berlin; Hirschwald 1858
  • 21 Bonfoco E, Leist M, Zhivotovsky B. et al . Cytoskeletal breakdown and apoptosis elicited by NO donors in cerebellar granule cells require NMDA receptor activation.  J Neurochem. 1996;  67 2484-2493
  • 22 Leist M, Single B, Naumann H. et al . Inhibition of mitochondrial ATP generation by nitric oxide switches apoptosis to necrosis.  Exp Cell Res. 1999;  249 396-403
  • 23 Zülch K J, Hossmann V. Patterns of cerebral infarctions. In: Vinken PJ, Bruyn GW, Klawans HL (eds) Handbook of Clinical Neurology, Vol. 53 (Revised Series 9). Amsterdam; Elsevier Science Publishers 1988: 175-198
  • 24 Matsuda H, Strebel F R, Kaneko T. et al . Apoptosis and necrosis occurring during different stages of primary and metastatic tumor growth of a rat mammary adenocarcinoma.  Anticancer Res. 1996;  16 1117-1121
  • 25 Sakamoto T, Repasky W T, Uchida K. et al . Modulation of cell death pathways to apoptosis and necrosis of H2O2-treated rat thymocytes by lipocortin I.  Biochem Biophys Res Commun. 1996;  220 643-647
  • 26 Shimizu S, Eguchi Y, Kamiike W. et al . Induction of apoptosis as well as necrosis by hypoxia and predominant prevention of apoptosis by Bcl-2 and Bcl-XL.  Cancer Research. 1996;  56 2161-2166
  • 27 Lieberthal W, Menza S A, Levine J S. Graded ATP depletion can cause necrosis or apoptosis of cultured mouse proximal tubular cells.  Am J Physiol Renal Physiol. 1998;  274 F315-F327
  • 28 Pender M P, Nguyen K B, McCombe P A, Kerr J F. Apoptosis in the nervous system in experimental allergic encephalomyelitis.  J Neurol Sci. 1991;  104 81-87
  • 29 Schmied M, Breitschopf H, Gold R. et al . Apoptosis of T lymphocytes in experimental autoimmune encephalomyelitis. Evidence for programmed cell death as a mechanism to control inflammation in the brain.  Am J Pathol. 1993;  143 446-452
  • 30 Barac-Latas V, Wege H, Lassmann H. Apoptosis of T-lymphocytes in Corona Virus induced encephalomyelitis.  Reg Immunol. 1995;  6 355-357
  • 31 Bauer J, Stadelmann C, Bancher C. et al . Apoptosis of T lymphocytes in acute disseminated encephalomyelitis.  Acta Neuropathol (Berl). 1999;  97 543-546
  • 32 Ozawa K, Suchanek G, Breitschopf H. et al . Patterns of oligodendroglia pathology in multiple sclerosis.  Brain. 1994;  117 1311-1322
  • 33 Zettl U K, Gold R, Hartung H P, Toyka K V. Apoptotic cell death of T-lymphocytes in experimental autoimmune neuritis of the Lewis rat.  Neurosci Let. 1994;  176 75-79
  • 34 Zettl U K, Gold R, Toyka K V, Hartung H P. In situ demonstration of T cell activation and elimination in the peripheral nervous system during experimental autoimmune neuritis in the Lewis rat.  Acta Neuropathol (Berl). 1996;  91 360-367
  • 35 Wekerle H, Linington C, Lassmann H, Meyermann R. Cellular immune reactivity within the CNS.  Trends Neurosci. 1986;  9 271-277
  • 36 Conti G, Scarpini E, Rostami A. et al . Schwann cell undergoes apoptosis during experimental allergic neuritis (EAN).  J Neurol Sci. 1998;  161 29-35
  • 37 Schneider C, Gold R, Dalakas M C. et al . MHC class I mediated cytotoxicity does not induce apoptosis in muscle fibers nor in inflammatory T cells: Studies in patients with polymyositis, dermatomyositis, and inclusion body myositis.  J Neuropathol Exp Neurol. 1996;  55 1205-1209
  • 38 Behrens L, Bender A, Johnson M A, Hohlfeld R. Cytotoxic mechanisms in inflammatory myopathies. Co-expression of Fas and protective Bcl-2 in muscle fibers and inflammatory cells.  Brain. 1997;  120 929-938
  • 39 Adler S, Zettl H, Bruck W. et al . The role of apoptotic cell death and bcl-2 protein expression in dermatomyositis.  Eur J Dermatol. 1997;  7 413-416
  • 40 Schneider C, Dalakas M C, Toyka K V. et al . T-cell apoptosis in inflammatory neuromuscular disorders associated with human immunodeficiency virus infection.  Arch Neurol. 1999;  56 79-83
  • 41 Schneider C, Matsumoto Y, Kohyama K. et al . Experimental autoimmune myositis in the Lewis rat: lack of spontaneous T-cell apoptosis and therapeutic response to glucocorticosteroid application.  J Neuroimmunol. 2000;  107 83-87
  • 42 Nau R, Zettl U, Gerber J. et al . Granulocytes in the subarachnoid space of humans and rabbits with bacterial meningitis undergo apoptosis and are eliminated by macrophages.  Acta Neuropathol (Berl). 1998;  96 472-480
  • 43 Gold R, Schmied M, Tontsch U. et al . Antigen presentation by astrocytes primes rat T lymphocytes for apoptotic cell death: A model for T cell apoptosis in vivo.  Brain. 1996;  119 651-659
  • 44 Smith T, Schmied M, Hewson A K. et al . Apoptosis of T cells and macrophages in the central nervous system of intact and adrenalectomized Lewis rats during experimental allergic encephalomyelitis.  J Autoimmun. 1996;  9 167-174
  • 45 Tabi Z, McCombe P A, Pender M P. Apoptotic elimination of V beta 8.2+ cells from the central nervous system during recovery from experimental autoimmune encephalomyelitis induced by the passive transfer of V beta 8.2+ encephalitogenic T cells.  Eur J Immunol. 1994;  24 2609-2617
  • 46 Bauer J, Bradl M, Hickley W F. et al . T-cell apoptosis in inflammatory brain lesions: destruction of T cells does not depend on antigen recognition (see comments).  Am J Pathol. 1998;  153 715-724
  • 47 Zipp F, Krammer P H, Weller M. Immune (dys)regulation in multiple sclerosis: role of the CD95/CD95 ligand system.  Immunol Today. 1999;  20 550-554
  • 48 Bachmann R, Eugster H P, Frei K. et al . Impairment of TNF-receptor-1 signaling but not Fas signaling diminishes T-cell apoptosis in myelin oligodendrocyte glycoprotein peptide-induced chronic demyelinating autoimmune encephalomyelitis in mice.  Am J Pathol. 1999;  154 1417-1422
  • 49 Zipp F, Weller M, Calabresi P A. et al . Increased serum levels of soluble CD95 (APO-1/Fas) in relapsing-remitting multiple sclerosis.  Ann Neurol. 1998;  43 116-120
  • 50 Pollard J D. A critical review of therapies in acute and chronic inflammatory demyelinating polyneuropathies.  Muscle Nerve. 1987;  10 214-221
  • 51 Gold R, Hartung H P, Toyka K V. Kortikosteroidtherapie neurologischer Autoimmunerkrankungen.  Münchn Med Wschr. 1995;  137 512-514
  • 52 Boumpas D T, Paliogianni F, Anastassiou E D, Ballow J E. Glucocorticosteroid action on the immune system: molecular and cellular aspects.  Clin Exp Rheumatol. 1991;  9 413-423
  • 53 Brann D W, Hendry L B, Mahesh V B. Emerging diversities in the mechanism of action of steroid hormones.  J Steroid Biochem Molec Biol. 1995;  52 113-133
  • 54 Buttgereit F, Wehling M, Burmester G R. A new hypothesis of modular glucocorticoid actions.  Arthritis Rheumat. 1998;  41 761-767
  • 55 Di Virgilio F, Chiozzi P, Falzoni S. et al . Cytolytic P2X purinoceptors.  Cell Death Differ. 1998;  5 191-199
  • 56 Zettl U K, Gold R, Toyka K V, Hartung H P. Intravenous glucocorticosteroid treatment augments apoptosis of inflammatory T cells in experimental autoimmune neuritis (EAN) of the Lewis rat.  J Neuropathol Exp Neurol. 1995;  54 540-547
  • 57 Schmidt J, Gold R, Schönrock L. et al . T-cell apoptosis in situ in experimental autoimmune encephalomyelitis following methylprednisolone pulse therapy.  Brain. 2000;  123 1431-1441
  • 58 Kaser A, Nagata S, Tilg H. Interferon alpha augments activation-induced T cell death by upregulation of Fas (CD95/APO-1) and Fas ligand expression.  Cytokine. 1999;  11 736-743
  • 59 Liblau R, Tisch R, Bercovici N, McDevitt H O. Systemic antigen in the treatment of T-cell-mediated autoimmune diseases.  Immunology Today. 1997;  18 599-604
  • 60 Critchfield J M, Racke M K, Zuniga Pflucker J C. et al . T cell deletion in high antigen dose therapy of autoimmune encephalomyelitis.  Science. 1994;  263 1139-1143
  • 61 Weishaupt A, Gold R, Giegerich G. et al . Antigen therapy eliminates T-cell inflammation by apoptosis: Effective treatment of experimental autoimmune neuritis with recombinant myelin protein P2.  Proc Natl Acad Sci USA. 1997;  94 1338-1342
  • 62 Weishaupt A, Gold R, Hartung T. et al . Role of TNF-alpha in high-dose antigen therapy in experimental autoimmune neuritis: Inhibition of TNF-alpha by neutralizing antibodies reduces T-cell apoptosis and prevents liver necrosis.  J Neuropathol Exp Neurol. 2000;  59 368-376
  • 63 The Lenercept Multiple Sclerosis Study Group and the University of British Columbia MS/MRI Analysis G roup. TNF neutralization in MS. Results of a randomized, placebo-controlled multicenter study.  Neurology. 1999;  53 457-465
  • 64 Scheff S W, DeKosky S T, Price D A. Quantitative assessment of cortical synaptic density in Alzheimer's disease.  Neurobiol Aging. 1990;  11 29-37
  • 65 Yamatsuji T, Matsui T, Okamoto T. et al . G protein-mediated neuronal DNA fragmentation induced by familial Alzheimer's disease-associated mutants of APP.  Science. 1996;  272 1349-1352
  • 66 Guo Q, Sopher B L, Furukawa K. et al . Alzheimer's presenilin mutation sensitizes neural cells to apoptosis induced by trophic factor withdrawal and amyloid beta-peptide: involvement of calcium and oxyradicals.  J Neurosci. 1997;  17 4212-4222
  • 67 Wolozin B, Iwasaki K, Vito P. et al . Participation of presenilin 2 in apoptosis: enhanced basal activity conferred by an Alzheimer mutation.  Science. 1996;  274 1710-1713
  • 68 Gschwind M, Huber G. Apoptotic cell death induced by beta-amyloid 1-42 peptide is cell type dependent.  J Neurochem. 1995;  65 292-300
  • 69 Li Y P, Bushnell A F, Lee C M. et al . Beta-amyloid induces apoptosis in human-derived neurotypic SH-SY5Y cells.  Brain Res. 1996;  738 196-204
  • 70 Kitamura Y, Shimohama S, Kamoshima W. et al . Changes of p53 in the brains of patients with Alzheimer's disease.  Biochem Biophys Res Commun. 1997;  232 418-421
  • 71 Kitamura Y, Shimohama S, Kamoshima W. et al . Alteration of proteins regulating apoptosis, Bcl-2, Bcl-x, Bax, Bak, Bad, ICH-1 and CPP32, in Alzheimer's disease.  Brain Res. 1998;  780 260-269
  • 72 Nishimura T, Akiyama H, Yonehara S. et al . Fas antigen expression in brains of patients with Alzheimer-type dementia.  Brain Res. 1995;  695 137-145
  • 73 Su J H, Cummings B J, Cotman C W. Plaque biogenesis in brain aging and Alzheimer's disease. I. Progressive changes in phosphorylation states of paired helical filaments and neurofilaments.  Brain Res. 1996;  739 79-87
  • 74 Su J H, Deng G, Cotman C W. Bax protein expression is increased in Alzheimer's brain: correlations with DNA damage, Bcl-2 expression, and brain pathology.  J Neuropathol Exp Neurol. 1997;  56 86-93
  • 75 Perry G, Nunomura A, Lucassen P. et al . Apoptosis and Alzheimer's disease (lettert).  Science. 1998;  282 1268-1269
  • 76 Perry G, Nunomura A, Smith M A. A suicide note from Alzheimer disease neurons? (news; comment).  Nat Med. 1998;  4 897-898
  • 77 Stadelmann C, Deckwerth T L, Srinivasan A. et al . Activation of caspase-3 in single neurons and autophagic granules of granulovacuolar degeneration in Alzheimer's disease - Evidence for apoptotic cell death.  Am J Pathol. 1999;  155 1459-1466
  • 78 Mattson M P. Apoptotic and anti-apoptotic synaptic signaling mechanisms.  Brain Pathol. 2000;  10 300-312
  • 79 Paulson H L. Toward an understanding of polyglutamine neurodegeneration.  Brain Pathol. 2000;  10 293-299
  • 80 Bruck Y, Bruck W, Kretzschmar H A, Lassmann H. Evidence for neuronal apoptosis in pontosubicular neuron necrosis.  Neuropathol Appl Neurobiol. 1996;  22 23-29
  • 81 Leist M, Nicotera P. Apoptosis, excitotoxicity, and neuropathology.  Exp Cell Res. 1998;  239 183-201
  • 82 Leist M, Single B, Castoldi A F. et al . Intracellular adenosine triphosphate (ATP) concentration: a switch in the decision between apoptosis and necrosis.  J Exp Med. 1997;  185 1481-1486
  • 83 Loddick S A, MacKenzie A, Rothwell N J. An ICE inhibitor, z-VAD-DCB attenuates ischaemic brain damage in the rat.  NeuroReport. 1996;  7 1465-1468
  • 84 Endres M, Namura S, Shimizu-Sasamata M. et al . Attenuation of delayed neuronal death after mild focal ischemia in mice by inhibition of the caspase family.  J Cereb Blood Flow Metab. 1998;  18 238-247
  • 85 Schulz J B, Weller M, Matthews R T. et al . Extended therapeutic window for caspase inhibition and synergy with MK-801 in the treatment of cerebral histotoxic hypoxia.  Cell Death Differ. 1998;  5 847-857
  • 86 Nicotera P, Leist M, Ferrando-May E. Intracellular ATP, a switch in the decision between apoptosis and necrosis.  Toxicol Lett. 1998;  103 139-142
  • 87 Schulz J B, Weller M, Moskowitz M A. Caspases as treatment targets in stroke and neurodegenerative diseases.  Ann Neurol. 1999;  45 421-429

Priv.-Doz. Dr. Ralf Gold

Neurologische Universitätsklinik

Josef-Schneider-Straße 11

97080 Würzburg

eMail: r.gold@mail.uni-wuerzburg.de

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