Journal Mobile Options
Table of Contents
Vol. 1, No. 1, 2004
Issue release date: April 2004
Neurodegenerative Dis 2004;1:9–19
(DOI:10.1159/000076665)

Neuronal Apoptosis in Neurodegenerative Diseases: From Basic Research to Clinical Application

Kermer P. · Liman J. · Weishaupt J.H. · Bähr M.
Department of Neurology, University of Göttingen, Göttingen, Germany
email Corresponding Author

Abstract

In recent years, the investigation of erroneous regulation of apoptotic mechanisms during acute and chronic injury of neuronal cells has gained increasing attention. Besides acute neuronal trauma and ischemia, chronic neurodegenerative diseases like Alzheimer’s, Huntington’s, Parkinson’s and Lou-Gehrig’s disease (amyotrophic lateral sclerosis) are of particular interest. The present article will provide an overview of basic apoptotic mechanisms, the contribution of neuronal apoptosis to the above-mentioned disorders, potential clinical applications and their limitations and the possible implications for future studies regarding these neurodegenerative diseases.


 goto top of outline Key Words

  • Apoptosis, neuronal
  • Caspases
  • Death effector domains
  • Neurodegeneration
  • Treatment, limitations

 goto top of outline Abstract

In recent years, the investigation of erroneous regulation of apoptotic mechanisms during acute and chronic injury of neuronal cells has gained increasing attention. Besides acute neuronal trauma and ischemia, chronic neurodegenerative diseases like Alzheimer’s, Huntington’s, Parkinson’s and Lou-Gehrig’s disease (amyotrophic lateral sclerosis) are of particular interest. The present article will provide an overview of basic apoptotic mechanisms, the contribution of neuronal apoptosis to the above-mentioned disorders, potential clinical applications and their limitations and the possible implications for future studies regarding these neurodegenerative diseases.

Copyright © 2004 S. Karger AG, Basel


 goto top of outline References
  1. Kerr JF, Wyllie AH, Currie AR: Apoptosis: A basic biological phenomenon with wide-ranging implications in tissue kinetics. Br J Cancer 1972;26:239–257.
  2. Portera-Cailliau C, Price DL, Martin LJ: Excitotoxic neuronal death in the immature brain is an apoptosis-necrosis morphological continuum. J Comp Neurol 1997;378:70–87.
  3. Portera-Cailliau C, Price DL, Martin LJ: Non-NMDA and NMDA receptor-mediated excitotoxic neuronal deaths in adult brain are morphologically distinct: Further evidence for an apoptosis-necrosis continuum. J Comp Neurol 1997;378:88–104.
  4. Martin LJ, Al-Abdulla NA, Brambrink AM, Kirsch JR, Sieber FE, Portera-Cailliau C: Neurodegeneration in excitotoxicity, global cerebral ischemia, and target deprivation: A perspective on the contributions of apoptosis and necrosis. Brain Res Bull 1998;46:281–309.
  5. Martin LJ: Neuronal cell death in nervous system development, disease, and injury. Int J Mol Med 2001;7:455–478.
  6. Mattson MP: Apoptosis in neurodegenerative disorders. Nat Rev Mol Cell Biol 2000;1:120–129.
  7. Barde YA: Trophic factors and neuronal survival. Neuron 1989;2:1525–1534.
  8. Mattson MP, Lindvall O: Neurotrophic factor and cytokine signaling in the aging brain; in Mattson MP, Geddes JW (eds): The Aging Brain. Greenwich, JAI Press, 1997, pp 299–345.
  9. Reed JC: Mechanisms of apoptosis. Am J Pathol 2000;157:1415–1430.
  10. Alnemri ES, Livingston DJ, Nicholson DW, Salvesen G, Thornberry NA, Wong WW, Yuan J: Human ICE/CED-3 protease nomenclature. Cell 1996;87:171.
  11. Reed JC: Apoptosis-based therapies. Nat Rev Drug Discov 2002;11:111–121.
  12. Velier JJ, Ellison JA, Kikly KK, Spera PA, Barone FC, Feuerstein GZ: Caspase-8 and caspase-3 are expressed by different populations of cortical neurons undergoing delayed cell death after focal stroke in the rat. J Neurosci 1999;19:5932–5941.
  13. Liepinsh E, Ilag LL, Otting G, Ibanez CF: NMR structure of the death domain of the p75 neurotrophin receptor. EMBO J 1997;16:4999–5005.
  14. Bredesen DE, Ye X, Tasinato A, Sperandio S, Wang JJ, Assa-Munt N, Rabizadeh S: p75NTR and the concept of cellular dependence: Seeing how the other half die. Cell Death Differ 1998;5:365–371.
  15. Hu B, Yip HK, So KF: Localization of p75 neurotrophin receptor in the retina of the adult SD rat: An immunocytochemical study at light and electron microscopic levels. Glia 1998;24:187–197.
  16. Hirsch S, Labes M, Bahr M: Changes in BDNF and neurotrophin receptor expression in degenerating and regenerating rat retinal ganglion cells. Restor Neurol Neurosci 2000;17:125–134.
  17. Yuan J, Yankner BA: Apoptosis in the nervous system. Nature 2000;407:802–809.
  18. Kroemer G, Reed JC: Mitochondrial control of cell death. Nat Med 2000;6:513–519.
  19. Reed JC: Cytochrome c: Can’t live with it – Can’t live without it. Cell 1997;91:559–562.
  20. Reed JC: Bcl-2 family proteins. Oncogene 1998;17:3225–3236.
  21. Wang HG, Pathan N, Ethell IM, Krajewski S, Yamaguchi Y, Shibasaki F, McKeon F, Bobo T, Franke TF, Reed JC: Ca2+-induced apoptosis through calcineurin dephosphorylation of BAD. Science 1999;284:339–343.
  22. Takayama S, Reed JC: Molecular chaperone targeting and regulation by BAG family proteins. Nat Cell Biol 2001;3:E237–E241.

    External Resources

  23. Kermer P, Krajewska M, Zapata JM, Takayama S, Mai J, Krajewski S, Reed JC: Bag1 is a regulator and marker of neuronal differentiation. Cell Death Differ 2002;9:405–413.
  24. Kermer P, Digicaylioglu MH, Kaul M, Zapata JM, Krajewska M, Stenner-Liewen F, Takayama S, Krajewski S, Lipton SA, Reed JC: BAG1 over-expression in the mouse brain protects against stroke. Brain Pathol 2003;13:495–506.
  25. Zhang H, Xu Q, Krajewski S, Krajewska M, Xie Z, Fuess S, Kitada S, Pawlowski K, Godzik A, Reed JC: BAR: An apoptosis regulator at the intersection of caspases and Bcl-2 family proteins. Proc Natl Acad Sci USA 2000;97:2597–2602.
  26. Roth W, Kermer P, Krajewska M, Krajewski S, Reed JC: Bifunctional apoptosis regulator (BAR) protects neurons from diverse cell death pathways. Cell Death Differ 2003;10:1178–1187.
  27. Xu Q, Reed JC: Bax inhibitor-1, a mammalian apoptosis suppressor identified by functional screening in yeast. Mol Cell 1998;1:337–346.
  28. Schmits R, Cochlovius B, Treitz G, Regitz E, Ketter R, Preuss KD, Romeike BF, Pfreundschuh M: Analysis of the antibody repertoire of astrocytoma patients against antigens expressed by gliomas. Int J Cancer 2002;98:73–77.
  29. Li P, Nijhawan D, Budihardjo I, Srinivasula SM, Ahmad M, Alnemri ES, Wang X: Cytochrome c and dATP-dependent formation of Apaf-1/caspase-9 complex initiates an apoptotic protease cascade. Cell 1997;91:479–489.
  30. Zou H, Li Y, Liu X, Wang X: An APAF-1.cytochrome c multimeric complex is a functional apoptosome that activates procaspase-9. J Biol Chem 1999;274:11549–11556.
  31. Qin H, Srinivasula SM, Wu G, Fernandes-Alnemri T, Alnemri ES, Shi Y: Structural basis of procaspase-9 recruitment by the apoptotic protease activating factor 1. Nature 1999;399:549–557.
  32. Salvesen GS, Dixit VM: Caspase activation: The induced-proximity model. Proc Natl Acad Sci USA 1999;96:10964–10967.
  33. Hengartner MO: The biochemistry of apoptosis. Nature 2000;407:770–776.
  34. Roy N, Mahadevan MS, McLean M, Shutler G, Yaraghi Z, Farahani R, Baird S, Besner-Johnston A, Lefebvre C, Kang X, et al: The gene for neuronal apoptosis inhibitory protein is partially deleted in individuals with spinal muscular atrophy. Cell 1995;80:167–178.
  35. Franke TF, Kaplan DR, Cantley LC: PI3K: Downstream AKTion blocks apoptosis. Cell 1997;88:435–437.
  36. Fukunaga K, Miyamoto E: Role of MAP kinase in neurons. Mol Neurobiol 1998;16:79–95.
  37. Bozyczko-Coyne D, Saporito MS, Hudkins RL: Targeting the JNK pathway for therapeutic benefit in CNS disease. Curr Drug Target CNS Neurol Disord 2002;1:31–49.
  38. Andersen JK: Does neuronal loss in Parkinson’s disease involve programmed cell death? Bioessays 2001;23:640–646.
  39. Fischer PP: Parkinson’s disease and the U.S. health care system. J Community Health Nurs 1999;16:191–204.
  40. Mochizuki H, Goto K, Mori H, Mizuno Y: Histochemical detection of apoptosis in Parkinson’s disease. J Neurol Sci 1996;137:120–123.
  41. Anglade P, Vyas S, Javoy-Agid F, Herrero MT, Michel PP, Marquez J, Mouatt- Prigent A, Ruberg M, Hirsch EC, Agid Y: Apoptosis and autophagy in nigral neurons of patients with Parkinson’s disease. Histol Histopathol 1997;12:25–31.
  42. Hirsch EC, Hunot S, Faucheux B, Agid Y, Mizuno Y, Mochizuki H, Tatton WG, Tatton N, Olanow WC: Dopaminergic neurons degenerate by apoptosis in Parkinson’s disease. Mov Disord 1999;14:383–385.
  43. Banati RB, Daniel SE, Blunt SB: Glial pathology but absence of apoptotic nigral neurons in long-standing Parkinson’s disease. Mov Disord 1998;13:221–227.
  44. Wüllner U, Kornhuber J, Weller M, Schulz JB, Loschmann PA, Riederer P, Klockgether T: Cell death and apoptosis regulating proteins in Parkinson’s disease – A cautionary note. Acta Neuropathol (Berl) 1999;97:408–412.
  45. Hartmann A, Hunot S, Michel PP, Muriel MP, Vyas S, Faucheux BA, Mouatt-Prigent A, Turmel H, Srinivasan A, Ruberg M, Evan GI, Agid Y, Hirsch EC: Caspase-3: A vulnerability factor and final effector in apoptotic death of dopaminergic neurons in Parkinson’s disease. Proc Natl Acad Sci USA 2000;97:2875–2880.
  46. Polymeropoulos MH: Genetics of Parkinson’s disease. Ann NY Acad Sci 2000;920:28–32.
  47. Giasson BI, Lee VM: Parkin and the molecular pathways of Parkinson’s disease. Neuron 2001;31:885–888.
  48. Imai Y, Soda M, Inoue H, Hattori N, Mizuno Y, Takahashi R: An unfolded putative transmembrane polypeptide, which can lead to endoplasmic reticulum stress, is a substrate of Parkin. Cell 2001;105:891–902.
  49. Perry TL, Yong VW: Idiopathic Parkinson’s disease, progressive supranuclear palsy and glutathione metabolism in the substantia nigra of patients. Neurosci Lett 1986;67:269–274.
  50. Jenner P, Olanow CW: Understanding cell death in Parkinson’s disease. Ann Neurol 1998;44(3 suppl 1):S72–S84.
  51. Merad-Boudia M, Nicole A, Santiard-Baron D, Saille C, Ceballos-Picot I: Mitochondrial impairment as an early event in the process of apoptosis induced by glutathione depletion in neuronal cells: Relevance to Parkinson’s disease. Biochem Pharmacol 1998;56:645–655.
  52. Nishi K: Expression of c-Jun in dopaminergic neurons of the substantia nigra in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated mice. Brain Res 1997;771:133–141.
  53. Saporito MS, Thomas BA, Scott RW: MPTP activates c-Jun NH(2)-terminal kinase (JNK) and its upstream regulatory kinase MKK4 in nigrostriatal neurons in vivo. J Neurochem 2000;75:1200–1208.
  54. Saporito MS, Brown EM, Miller MS, Carswell S: CEP-1347/KT-7515, an inhibitor of c-jun N-terminal kinase activation, attenuates the 1-methyl-4-phenyl tetrahydropyridine-mediated loss of nigrostriatal dopaminergic neurons In vivo. J Pharmacol Exp Ther 1999;288:421–427.
  55. Eberhardt O, Coelln RV, Kugler S, Lindenau J, Rathke-Hartlieb S, Gerhardt E, Haid S, Isenmann S, Gravel C, Srinivasan A, Bahr M, Weller M, Dichgans J, Schulz JB: Protection by synergistic effects of adenovirus-mediated X chromosome-linked inhibitor of apoptosis and glial cell line-derived neurotrophic factor gene transfer in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine model of Parkinson’s disease. J Neurosci 2000;20:9126–9134.
  56. Kahns S, Lykkebo S, Jakobsen LD, Nielsen MS, Jensen PH: Caspase-mediated parkin cleavage in apoptotic cell death. J Biol Chem 2002;277:15303–15308.
  57. Ho LW, Carmichael J, Swartz J, Wyttenbach A, Rankin J, Rubinsztein DC: The molecular biology of Huntington’s disease. Psychol Med 2001;31:3–14.
  58. Rubinsztein DC, Leggo J, Coles R, Almqvist E, Biancalana V, Cassiman JJ, Chotai K, Connarty M, Crauford D, Curtis A, Curtis D, Davidson MJ, Differ AM, Dode C, Dodge A, Frontali M, Ranen NG, Stine OC, Sherr M, Abbott MH, Franz ML, Graham CA, Harper PS, Hedreen JC, Hayden MR, et al: Phenotypic characterization of individuals with 30–40 CAG repeats in the Huntington disease (HD) gene reveals HD cases with 36 repeats and apparently normal elderly individuals with 36–39 repeats. Am J Hum Genet 1996;59:16–22.
  59. Ross CA, Hayden MR: Huntington’s disease; in Rubinsztein DC, Hayden MR (eds): Analysis of Triplet Repeat Disorders. Oxford, Bios Scientific, 1998, pp 169–208..
  60. Dragunow M, Faull RL, Lawlor P, Beilharz EJ, Singleton K, Walker EB, Mee E: In situ evidence for DNA fragmentation in Huntington’s disease striatum and Alzheimer’s disease temporal lobes. Neuroreport 1995;6:1053–1057.
  61. Portera-Cailliau C, Hedreen JC, Price DL, Koliatsos VE: Evidence for apoptotic cell death in Huntington disease and excitotoxic animal models. J Neurosci 1995;15(5 Pt 2):3775–3787.
  62. Thomas LB, Gates DJ, Richfield EK, O’Brien TF, Schweitzer JB, Steindler DA: DNA end labeling (TUNEL) in Huntington’s disease and other neuropathological conditions. Exp Neurol 1995;133:265–272.
  63. Liu YF: Expression of polyglutamine-expanded Huntingtin activates the SEK1-JNK pathway and induces apoptosis in a hippocampal neuronal cell line. J Biol Chem 1998;273:28873–28877.
  64. Davies S, Ramsden DB: Huntington’s disease. Mol Pathol 2001;54:409–413.
  65. Sieradzan KA, Mann DM: The selective vulnerability of nerve cells in Huntington’s disease. Neuropathol Appl Neurobiol 2001;27:1–21.
  66. Goldberg YP, Nicholson DW, Rasper DM, Kalchman MA, Koide HB, Graham RK, Bromm M, Kazemi-Esfarjani P, Thornberry NA, Vaillancourt JP, Hayden MR: Cleavage of huntingtin by apopain, a proapoptotic cysteine protease, is modulated by the polyglutamine tract. Nat Genet 1996;13:442–449.
  67. Wellington CL, Ellerby LM, Hackam AS, Margolis RL, Trifiro MA, Singaraja R, McCutcheon K, Salvesen GS, Propp SS, Bromm M, Rowland KJ, Zhang T, Rasper D, Roy S, Thornberry N, Pinsky L, Kakizuka A, Ross CA, Nicholson DW, Bredesen DE, Hayden MR: Caspase cleavage of gene products associated with triplet expansion disorders generates truncated fragments containing the polyglutamine tract. J Biol Chem 1998;273:9158–9167.
  68. Ona VO, Li M, Vonsattel JP, Andrews LJ, Khan SQ, Chung WM, Frey AS, Menon AS, Li XJ, Stieg PE, Yuan J, Penney JB, Young AB, Cha JH, Friedlander RM: Inhibition of caspase-1 slows disease progression in a mouse model of Huntington’s disease. Nature 1999;399:263–267.
  69. Kalchman MA, Koide HB, McCutcheon K, Graham RK, Nichol K, Nishiyama K, Kazemi-Esfarjani P, Lynn FC, Wellington C, Metzler M, Goldberg YP, Kanazawa I, Gietz RD, Hayden MR: HIP1, a human homologue of S. cerevisiae Sla2p, interacts with membrane-associated huntingtin in the brain. Nat Genet 1997;16:44–53.
  70. Gervais FG, Singaraja R, Xanthoudakis S, Gutekunst CA, Leavitt BR, Metzler M, Hackam AS, Tam J, Vaillancourt JP, Houtzager V, Rasper DM, Roy S, Hayden MR, Nicholson DW: Recruitment and activation of caspase-8 by the Huntingtin-interacting protein Hip-1 and a novel partner Hippi. Nat Cell Biol 2002;4:95–105.
  71. Sathasivam S, Ince PG, Shaw PJ: Apoptosis in amyotrophic lateral sclerosis: A review of the evidence. Neuropathol Appl Neurobiol 2001;27:257–274.
  72. Troost D, Aten J, Morsink F, de Jong JM: Apoptosis in amyotrophic lateral sclerosis is not restricted to motor neurons. Bcl-2 expression is increased in unaffected post-central gyrus. Neuropathol Appl Neurobiol 1995;21:498–504.
  73. Mu X, He J, Anderson DW, Trojanowski JQ, Springer JE: Altered expression of bcl-2 and bax mRNA in amyotrophic lateral sclerosis spinal cord motor neurons. Ann Neurol 1996;40:379–386.
  74. Ekegren T, Grundstrom E, Lindholm D, Aquilonius SM: Upregulation of Bax protein and increased DNA degradation in ALS spinal cord motor neurons. Acta Neurol Scand 1999;100:317–321.
  75. Martin LJ: Neuronal death in amyotrophic lateral sclerosis is apoptosis: Possible contribution of a programmed cell death mechanism. J Neuropathol Exp Neurol 1999;58:459–471.
  76. Li M, Ona VO, Guegan C, Chen M, Jackson-Lewis V, Andrews LJ, Olszewski AJ, Stieg PE, Lee JP, Przedborski S, Friedlander RM: Functional role of caspase-1 and caspase-3 in an ALS transgenic mouse model. Science 2000;288:335–339.
  77. Vukosavic S, Stefanis L, Jackson-Lewis V, Guegan C, Romero N, Chen C, Dubois-Dauphin M, Przedborski S: Delaying caspase activation by Bcl-2: A clue to disease retardation in a transgenic mouse model of amyotrophic lateral sclerosis. J Neurosci 2000;20:9119–9125.
  78. Antuono P, Beyer J: The burden of dementia. A medical and research perspective. Theor Med Bioeth 1999;20:3–13.
  79. Roth KA: Caspases, apoptosis, and Alzheimer disease: Causation, correlation, and confusion. J Neuropathol Exp Neurol 2001;60:829–838.
  80. Mattson MP, Duan W, Pedersen WA, Culmsee C: Neurodegenerative disorders and ischemic brain diseases. Apoptosis 2001;6:69–81.
  81. Phillips HS, Hains JM, Armanini M, Laramee GR, Johnson SA, Winslow JW: BDNF mRNA is decreased in the hippocampus of individuals with Alzheimer’s disease. Neuron 1991;7:695–702.
  82. Mufson EJ, Kordower JH: Cortical neurons express nerve growth factor receptors in advanced age and Alzheimer disease. Proc Natl Acad Sci USA 1992;89:569–573.
  83. Kermer P, Bähr M: Prävention neuronaler Apoptose: Implikationen für die Therapie neurodegenerativer Erkrankungen. Neuroforum 2002;2:193–199.
  84. Gortelmeyer R, Erbler H: Memantine in the treatment of mild to moderate dementia syndrome. A double-blind placebo-controlled study. Arzneimittelforschung 1992;42:904–913.
  85. Oertel WH, Bandmann O: Multiple system atrophy. J Neural Transm Suppl 1999;56:155–164.
  86. Becker-Hapak M, McAllister SS, Dowdy SF: TAT-mediated protein transduction into mammalian cells. Methods 2001;24:247–256.
  87. Ford KG, Souberbielle BE, Darling D, Farzaneh F: Protein transduction: An alternative to genetic intervention? Gene Ther 2001;8:1–4.
  88. Kilic U, Kilic E, Dietz GP, Bähr M: Intravenous TAT-GDNF is protective after focal cerebral ischemia in mice. Stroke 2003;34:1304–1310.
  89. Baekelandt V, De Strooper B, Nuttin B, Debyser Z: Gene therapeutic strategies for neurodegenerative diseases. Curr Opin Mol Ther 2000;2:540–554.
  90. Estibeiro P, Godfray J: Antisense as a neuroscience tool and therapeutic agent. Trends Neurosci 2001;24(suppl):S56–S62.

    External Resources

  91. Hock C, Konietzko U, Papassotiropoulos A, Wollmer A, Streffer J, von Rotz RC, Davey G, Moritz E, Nitsch RM: Generation of antibodies specific for beta-amyloid by vaccination of patients with Alzheimer disease. Nat Med 2002;8:1270–1275.

 goto top of outline Author Contacts

Dr. Pawel Kermer
Department of Neurology, University of Göttingen
Robert-Koch-Strasse 40
DE–37075 Göttingen (Germany)
Tel. +49 551 394 927, Fax +49 551 391 4302, E-Mail pkermer@gwdg.de


 goto top of outline Article Information

Received: August 28, 2003
Accepted after revision: October 9, 2003
Number of Print Pages : 11
Number of Figures : 2, Number of Tables : 1, Number of References : 91


 goto top of outline Publication Details

Neurodegenerative Diseases

Vol. 1, No. 1, Year 2004 (Cover Date: Released April 2004)

Journal Editor: R.M. Nitsch, Zürich; C. Hock, Zürich
ISSN: 1660–2854 (print), 1660–2862 (Online)

For additional information: http://www.karger.com/ndd


Copyright / Drug Dosage / Disclaimer

Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher or, in the case of photocopying, direct payment of a specified fee to the Copyright Clearance Center.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in goverment regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

Abstract

In recent years, the investigation of erroneous regulation of apoptotic mechanisms during acute and chronic injury of neuronal cells has gained increasing attention. Besides acute neuronal trauma and ischemia, chronic neurodegenerative diseases like Alzheimer’s, Huntington’s, Parkinson’s and Lou-Gehrig’s disease (amyotrophic lateral sclerosis) are of particular interest. The present article will provide an overview of basic apoptotic mechanisms, the contribution of neuronal apoptosis to the above-mentioned disorders, potential clinical applications and their limitations and the possible implications for future studies regarding these neurodegenerative diseases.



 goto top of outline Author Contacts

Dr. Pawel Kermer
Department of Neurology, University of Göttingen
Robert-Koch-Strasse 40
DE–37075 Göttingen (Germany)
Tel. +49 551 394 927, Fax +49 551 391 4302, E-Mail pkermer@gwdg.de


 goto top of outline Article Information

Received: August 28, 2003
Accepted after revision: October 9, 2003
Number of Print Pages : 11
Number of Figures : 2, Number of Tables : 1, Number of References : 91


 goto top of outline Publication Details

Neurodegenerative Diseases

Vol. 1, No. 1, Year 2004 (Cover Date: Released April 2004)

Journal Editor: R.M. Nitsch, Zürich; C. Hock, Zürich
ISSN: 1660–2854 (print), 1660–2862 (Online)

For additional information: http://www.karger.com/ndd


Copyright / Drug Dosage

Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher or, in the case of photocopying, direct payment of a specified fee to the Copyright Clearance Center.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in goverment regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

References

  1. Kerr JF, Wyllie AH, Currie AR: Apoptosis: A basic biological phenomenon with wide-ranging implications in tissue kinetics. Br J Cancer 1972;26:239–257.
  2. Portera-Cailliau C, Price DL, Martin LJ: Excitotoxic neuronal death in the immature brain is an apoptosis-necrosis morphological continuum. J Comp Neurol 1997;378:70–87.
  3. Portera-Cailliau C, Price DL, Martin LJ: Non-NMDA and NMDA receptor-mediated excitotoxic neuronal deaths in adult brain are morphologically distinct: Further evidence for an apoptosis-necrosis continuum. J Comp Neurol 1997;378:88–104.
  4. Martin LJ, Al-Abdulla NA, Brambrink AM, Kirsch JR, Sieber FE, Portera-Cailliau C: Neurodegeneration in excitotoxicity, global cerebral ischemia, and target deprivation: A perspective on the contributions of apoptosis and necrosis. Brain Res Bull 1998;46:281–309.
  5. Martin LJ: Neuronal cell death in nervous system development, disease, and injury. Int J Mol Med 2001;7:455–478.
  6. Mattson MP: Apoptosis in neurodegenerative disorders. Nat Rev Mol Cell Biol 2000;1:120–129.
  7. Barde YA: Trophic factors and neuronal survival. Neuron 1989;2:1525–1534.
  8. Mattson MP, Lindvall O: Neurotrophic factor and cytokine signaling in the aging brain; in Mattson MP, Geddes JW (eds): The Aging Brain. Greenwich, JAI Press, 1997, pp 299–345.
  9. Reed JC: Mechanisms of apoptosis. Am J Pathol 2000;157:1415–1430.
  10. Alnemri ES, Livingston DJ, Nicholson DW, Salvesen G, Thornberry NA, Wong WW, Yuan J: Human ICE/CED-3 protease nomenclature. Cell 1996;87:171.
  11. Reed JC: Apoptosis-based therapies. Nat Rev Drug Discov 2002;11:111–121.
  12. Velier JJ, Ellison JA, Kikly KK, Spera PA, Barone FC, Feuerstein GZ: Caspase-8 and caspase-3 are expressed by different populations of cortical neurons undergoing delayed cell death after focal stroke in the rat. J Neurosci 1999;19:5932–5941.
  13. Liepinsh E, Ilag LL, Otting G, Ibanez CF: NMR structure of the death domain of the p75 neurotrophin receptor. EMBO J 1997;16:4999–5005.
  14. Bredesen DE, Ye X, Tasinato A, Sperandio S, Wang JJ, Assa-Munt N, Rabizadeh S: p75NTR and the concept of cellular dependence: Seeing how the other half die. Cell Death Differ 1998;5:365–371.
  15. Hu B, Yip HK, So KF: Localization of p75 neurotrophin receptor in the retina of the adult SD rat: An immunocytochemical study at light and electron microscopic levels. Glia 1998;24:187–197.
  16. Hirsch S, Labes M, Bahr M: Changes in BDNF and neurotrophin receptor expression in degenerating and regenerating rat retinal ganglion cells. Restor Neurol Neurosci 2000;17:125–134.
  17. Yuan J, Yankner BA: Apoptosis in the nervous system. Nature 2000;407:802–809.
  18. Kroemer G, Reed JC: Mitochondrial control of cell death. Nat Med 2000;6:513–519.
  19. Reed JC: Cytochrome c: Can’t live with it – Can’t live without it. Cell 1997;91:559–562.
  20. Reed JC: Bcl-2 family proteins. Oncogene 1998;17:3225–3236.
  21. Wang HG, Pathan N, Ethell IM, Krajewski S, Yamaguchi Y, Shibasaki F, McKeon F, Bobo T, Franke TF, Reed JC: Ca2+-induced apoptosis through calcineurin dephosphorylation of BAD. Science 1999;284:339–343.
  22. Takayama S, Reed JC: Molecular chaperone targeting and regulation by BAG family proteins. Nat Cell Biol 2001;3:E237–E241.

    External Resources

  23. Kermer P, Krajewska M, Zapata JM, Takayama S, Mai J, Krajewski S, Reed JC: Bag1 is a regulator and marker of neuronal differentiation. Cell Death Differ 2002;9:405–413.
  24. Kermer P, Digicaylioglu MH, Kaul M, Zapata JM, Krajewska M, Stenner-Liewen F, Takayama S, Krajewski S, Lipton SA, Reed JC: BAG1 over-expression in the mouse brain protects against stroke. Brain Pathol 2003;13:495–506.
  25. Zhang H, Xu Q, Krajewski S, Krajewska M, Xie Z, Fuess S, Kitada S, Pawlowski K, Godzik A, Reed JC: BAR: An apoptosis regulator at the intersection of caspases and Bcl-2 family proteins. Proc Natl Acad Sci USA 2000;97:2597–2602.
  26. Roth W, Kermer P, Krajewska M, Krajewski S, Reed JC: Bifunctional apoptosis regulator (BAR) protects neurons from diverse cell death pathways. Cell Death Differ 2003;10:1178–1187.
  27. Xu Q, Reed JC: Bax inhibitor-1, a mammalian apoptosis suppressor identified by functional screening in yeast. Mol Cell 1998;1:337–346.
  28. Schmits R, Cochlovius B, Treitz G, Regitz E, Ketter R, Preuss KD, Romeike BF, Pfreundschuh M: Analysis of the antibody repertoire of astrocytoma patients against antigens expressed by gliomas. Int J Cancer 2002;98:73–77.
  29. Li P, Nijhawan D, Budihardjo I, Srinivasula SM, Ahmad M, Alnemri ES, Wang X: Cytochrome c and dATP-dependent formation of Apaf-1/caspase-9 complex initiates an apoptotic protease cascade. Cell 1997;91:479–489.
  30. Zou H, Li Y, Liu X, Wang X: An APAF-1.cytochrome c multimeric complex is a functional apoptosome that activates procaspase-9. J Biol Chem 1999;274:11549–11556.
  31. Qin H, Srinivasula SM, Wu G, Fernandes-Alnemri T, Alnemri ES, Shi Y: Structural basis of procaspase-9 recruitment by the apoptotic protease activating factor 1. Nature 1999;399:549–557.
  32. Salvesen GS, Dixit VM: Caspase activation: The induced-proximity model. Proc Natl Acad Sci USA 1999;96:10964–10967.
  33. Hengartner MO: The biochemistry of apoptosis. Nature 2000;407:770–776.
  34. Roy N, Mahadevan MS, McLean M, Shutler G, Yaraghi Z, Farahani R, Baird S, Besner-Johnston A, Lefebvre C, Kang X, et al: The gene for neuronal apoptosis inhibitory protein is partially deleted in individuals with spinal muscular atrophy. Cell 1995;80:167–178.
  35. Franke TF, Kaplan DR, Cantley LC: PI3K: Downstream AKTion blocks apoptosis. Cell 1997;88:435–437.
  36. Fukunaga K, Miyamoto E: Role of MAP kinase in neurons. Mol Neurobiol 1998;16:79–95.
  37. Bozyczko-Coyne D, Saporito MS, Hudkins RL: Targeting the JNK pathway for therapeutic benefit in CNS disease. Curr Drug Target CNS Neurol Disord 2002;1:31–49.
  38. Andersen JK: Does neuronal loss in Parkinson’s disease involve programmed cell death? Bioessays 2001;23:640–646.
  39. Fischer PP: Parkinson’s disease and the U.S. health care system. J Community Health Nurs 1999;16:191–204.
  40. Mochizuki H, Goto K, Mori H, Mizuno Y: Histochemical detection of apoptosis in Parkinson’s disease. J Neurol Sci 1996;137:120–123.
  41. Anglade P, Vyas S, Javoy-Agid F, Herrero MT, Michel PP, Marquez J, Mouatt- Prigent A, Ruberg M, Hirsch EC, Agid Y: Apoptosis and autophagy in nigral neurons of patients with Parkinson’s disease. Histol Histopathol 1997;12:25–31.
  42. Hirsch EC, Hunot S, Faucheux B, Agid Y, Mizuno Y, Mochizuki H, Tatton WG, Tatton N, Olanow WC: Dopaminergic neurons degenerate by apoptosis in Parkinson’s disease. Mov Disord 1999;14:383–385.
  43. Banati RB, Daniel SE, Blunt SB: Glial pathology but absence of apoptotic nigral neurons in long-standing Parkinson’s disease. Mov Disord 1998;13:221–227.
  44. Wüllner U, Kornhuber J, Weller M, Schulz JB, Loschmann PA, Riederer P, Klockgether T: Cell death and apoptosis regulating proteins in Parkinson’s disease – A cautionary note. Acta Neuropathol (Berl) 1999;97:408–412.
  45. Hartmann A, Hunot S, Michel PP, Muriel MP, Vyas S, Faucheux BA, Mouatt-Prigent A, Turmel H, Srinivasan A, Ruberg M, Evan GI, Agid Y, Hirsch EC: Caspase-3: A vulnerability factor and final effector in apoptotic death of dopaminergic neurons in Parkinson’s disease. Proc Natl Acad Sci USA 2000;97:2875–2880.
  46. Polymeropoulos MH: Genetics of Parkinson’s disease. Ann NY Acad Sci 2000;920:28–32.
  47. Giasson BI, Lee VM: Parkin and the molecular pathways of Parkinson’s disease. Neuron 2001;31:885–888.
  48. Imai Y, Soda M, Inoue H, Hattori N, Mizuno Y, Takahashi R: An unfolded putative transmembrane polypeptide, which can lead to endoplasmic reticulum stress, is a substrate of Parkin. Cell 2001;105:891–902.
  49. Perry TL, Yong VW: Idiopathic Parkinson’s disease, progressive supranuclear palsy and glutathione metabolism in the substantia nigra of patients. Neurosci Lett 1986;67:269–274.
  50. Jenner P, Olanow CW: Understanding cell death in Parkinson’s disease. Ann Neurol 1998;44(3 suppl 1):S72–S84.
  51. Merad-Boudia M, Nicole A, Santiard-Baron D, Saille C, Ceballos-Picot I: Mitochondrial impairment as an early event in the process of apoptosis induced by glutathione depletion in neuronal cells: Relevance to Parkinson’s disease. Biochem Pharmacol 1998;56:645–655.
  52. Nishi K: Expression of c-Jun in dopaminergic neurons of the substantia nigra in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated mice. Brain Res 1997;771:133–141.
  53. Saporito MS, Thomas BA, Scott RW: MPTP activates c-Jun NH(2)-terminal kinase (JNK) and its upstream regulatory kinase MKK4 in nigrostriatal neurons in vivo. J Neurochem 2000;75:1200–1208.
  54. Saporito MS, Brown EM, Miller MS, Carswell S: CEP-1347/KT-7515, an inhibitor of c-jun N-terminal kinase activation, attenuates the 1-methyl-4-phenyl tetrahydropyridine-mediated loss of nigrostriatal dopaminergic neurons In vivo. J Pharmacol Exp Ther 1999;288:421–427.
  55. Eberhardt O, Coelln RV, Kugler S, Lindenau J, Rathke-Hartlieb S, Gerhardt E, Haid S, Isenmann S, Gravel C, Srinivasan A, Bahr M, Weller M, Dichgans J, Schulz JB: Protection by synergistic effects of adenovirus-mediated X chromosome-linked inhibitor of apoptosis and glial cell line-derived neurotrophic factor gene transfer in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine model of Parkinson’s disease. J Neurosci 2000;20:9126–9134.
  56. Kahns S, Lykkebo S, Jakobsen LD, Nielsen MS, Jensen PH: Caspase-mediated parkin cleavage in apoptotic cell death. J Biol Chem 2002;277:15303–15308.
  57. Ho LW, Carmichael J, Swartz J, Wyttenbach A, Rankin J, Rubinsztein DC: The molecular biology of Huntington’s disease. Psychol Med 2001;31:3–14.
  58. Rubinsztein DC, Leggo J, Coles R, Almqvist E, Biancalana V, Cassiman JJ, Chotai K, Connarty M, Crauford D, Curtis A, Curtis D, Davidson MJ, Differ AM, Dode C, Dodge A, Frontali M, Ranen NG, Stine OC, Sherr M, Abbott MH, Franz ML, Graham CA, Harper PS, Hedreen JC, Hayden MR, et al: Phenotypic characterization of individuals with 30–40 CAG repeats in the Huntington disease (HD) gene reveals HD cases with 36 repeats and apparently normal elderly individuals with 36–39 repeats. Am J Hum Genet 1996;59:16–22.
  59. Ross CA, Hayden MR: Huntington’s disease; in Rubinsztein DC, Hayden MR (eds): Analysis of Triplet Repeat Disorders. Oxford, Bios Scientific, 1998, pp 169–208..
  60. Dragunow M, Faull RL, Lawlor P, Beilharz EJ, Singleton K, Walker EB, Mee E: In situ evidence for DNA fragmentation in Huntington’s disease striatum and Alzheimer’s disease temporal lobes. Neuroreport 1995;6:1053–1057.
  61. Portera-Cailliau C, Hedreen JC, Price DL, Koliatsos VE: Evidence for apoptotic cell death in Huntington disease and excitotoxic animal models. J Neurosci 1995;15(5 Pt 2):3775–3787.
  62. Thomas LB, Gates DJ, Richfield EK, O’Brien TF, Schweitzer JB, Steindler DA: DNA end labeling (TUNEL) in Huntington’s disease and other neuropathological conditions. Exp Neurol 1995;133:265–272.
  63. Liu YF: Expression of polyglutamine-expanded Huntingtin activates the SEK1-JNK pathway and induces apoptosis in a hippocampal neuronal cell line. J Biol Chem 1998;273:28873–28877.
  64. Davies S, Ramsden DB: Huntington’s disease. Mol Pathol 2001;54:409–413.
  65. Sieradzan KA, Mann DM: The selective vulnerability of nerve cells in Huntington’s disease. Neuropathol Appl Neurobiol 2001;27:1–21.
  66. Goldberg YP, Nicholson DW, Rasper DM, Kalchman MA, Koide HB, Graham RK, Bromm M, Kazemi-Esfarjani P, Thornberry NA, Vaillancourt JP, Hayden MR: Cleavage of huntingtin by apopain, a proapoptotic cysteine protease, is modulated by the polyglutamine tract. Nat Genet 1996;13:442–449.
  67. Wellington CL, Ellerby LM, Hackam AS, Margolis RL, Trifiro MA, Singaraja R, McCutcheon K, Salvesen GS, Propp SS, Bromm M, Rowland KJ, Zhang T, Rasper D, Roy S, Thornberry N, Pinsky L, Kakizuka A, Ross CA, Nicholson DW, Bredesen DE, Hayden MR: Caspase cleavage of gene products associated with triplet expansion disorders generates truncated fragments containing the polyglutamine tract. J Biol Chem 1998;273:9158–9167.
  68. Ona VO, Li M, Vonsattel JP, Andrews LJ, Khan SQ, Chung WM, Frey AS, Menon AS, Li XJ, Stieg PE, Yuan J, Penney JB, Young AB, Cha JH, Friedlander RM: Inhibition of caspase-1 slows disease progression in a mouse model of Huntington’s disease. Nature 1999;399:263–267.
  69. Kalchman MA, Koide HB, McCutcheon K, Graham RK, Nichol K, Nishiyama K, Kazemi-Esfarjani P, Lynn FC, Wellington C, Metzler M, Goldberg YP, Kanazawa I, Gietz RD, Hayden MR: HIP1, a human homologue of S. cerevisiae Sla2p, interacts with membrane-associated huntingtin in the brain. Nat Genet 1997;16:44–53.
  70. Gervais FG, Singaraja R, Xanthoudakis S, Gutekunst CA, Leavitt BR, Metzler M, Hackam AS, Tam J, Vaillancourt JP, Houtzager V, Rasper DM, Roy S, Hayden MR, Nicholson DW: Recruitment and activation of caspase-8 by the Huntingtin-interacting protein Hip-1 and a novel partner Hippi. Nat Cell Biol 2002;4:95–105.
  71. Sathasivam S, Ince PG, Shaw PJ: Apoptosis in amyotrophic lateral sclerosis: A review of the evidence. Neuropathol Appl Neurobiol 2001;27:257–274.
  72. Troost D, Aten J, Morsink F, de Jong JM: Apoptosis in amyotrophic lateral sclerosis is not restricted to motor neurons. Bcl-2 expression is increased in unaffected post-central gyrus. Neuropathol Appl Neurobiol 1995;21:498–504.
  73. Mu X, He J, Anderson DW, Trojanowski JQ, Springer JE: Altered expression of bcl-2 and bax mRNA in amyotrophic lateral sclerosis spinal cord motor neurons. Ann Neurol 1996;40:379–386.
  74. Ekegren T, Grundstrom E, Lindholm D, Aquilonius SM: Upregulation of Bax protein and increased DNA degradation in ALS spinal cord motor neurons. Acta Neurol Scand 1999;100:317–321.
  75. Martin LJ: Neuronal death in amyotrophic lateral sclerosis is apoptosis: Possible contribution of a programmed cell death mechanism. J Neuropathol Exp Neurol 1999;58:459–471.
  76. Li M, Ona VO, Guegan C, Chen M, Jackson-Lewis V, Andrews LJ, Olszewski AJ, Stieg PE, Lee JP, Przedborski S, Friedlander RM: Functional role of caspase-1 and caspase-3 in an ALS transgenic mouse model. Science 2000;288:335–339.
  77. Vukosavic S, Stefanis L, Jackson-Lewis V, Guegan C, Romero N, Chen C, Dubois-Dauphin M, Przedborski S: Delaying caspase activation by Bcl-2: A clue to disease retardation in a transgenic mouse model of amyotrophic lateral sclerosis. J Neurosci 2000;20:9119–9125.
  78. Antuono P, Beyer J: The burden of dementia. A medical and research perspective. Theor Med Bioeth 1999;20:3–13.
  79. Roth KA: Caspases, apoptosis, and Alzheimer disease: Causation, correlation, and confusion. J Neuropathol Exp Neurol 2001;60:829–838.
  80. Mattson MP, Duan W, Pedersen WA, Culmsee C: Neurodegenerative disorders and ischemic brain diseases. Apoptosis 2001;6:69–81.
  81. Phillips HS, Hains JM, Armanini M, Laramee GR, Johnson SA, Winslow JW: BDNF mRNA is decreased in the hippocampus of individuals with Alzheimer’s disease. Neuron 1991;7:695–702.
  82. Mufson EJ, Kordower JH: Cortical neurons express nerve growth factor receptors in advanced age and Alzheimer disease. Proc Natl Acad Sci USA 1992;89:569–573.
  83. Kermer P, Bähr M: Prävention neuronaler Apoptose: Implikationen für die Therapie neurodegenerativer Erkrankungen. Neuroforum 2002;2:193–199.
  84. Gortelmeyer R, Erbler H: Memantine in the treatment of mild to moderate dementia syndrome. A double-blind placebo-controlled study. Arzneimittelforschung 1992;42:904–913.
  85. Oertel WH, Bandmann O: Multiple system atrophy. J Neural Transm Suppl 1999;56:155–164.
  86. Becker-Hapak M, McAllister SS, Dowdy SF: TAT-mediated protein transduction into mammalian cells. Methods 2001;24:247–256.
  87. Ford KG, Souberbielle BE, Darling D, Farzaneh F: Protein transduction: An alternative to genetic intervention? Gene Ther 2001;8:1–4.
  88. Kilic U, Kilic E, Dietz GP, Bähr M: Intravenous TAT-GDNF is protective after focal cerebral ischemia in mice. Stroke 2003;34:1304–1310.
  89. Baekelandt V, De Strooper B, Nuttin B, Debyser Z: Gene therapeutic strategies for neurodegenerative diseases. Curr Opin Mol Ther 2000;2:540–554.
  90. Estibeiro P, Godfray J: Antisense as a neuroscience tool and therapeutic agent. Trends Neurosci 2001;24(suppl):S56–S62.

    External Resources

  91. Hock C, Konietzko U, Papassotiropoulos A, Wollmer A, Streffer J, von Rotz RC, Davey G, Moritz E, Nitsch RM: Generation of antibodies specific for beta-amyloid by vaccination of patients with Alzheimer disease. Nat Med 2002;8:1270–1275.