Skip to main content
SpringerLink
Log in

Caspases in ischaemic brain injury and neurodegenerative disease

  • Published:
Apoptosis Aims and scope Submit manuscript

Abstract

The importance of caspases in developmental neuronal death is well-established. Recent data provide compelling evidence of caspase activation after ischaemic brain injury. Caspase inhibitors reduce cell death in several models of ischaemic injury. This review summarizes our current understanding of caspase function in ischaemic brain injury and examines the accumulating evidence of caspase participation in several neurodegenerative diseases. The therapeutic consequences of caspase inhibitor treatment in reducing cell death after such injury are also discussed.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Choi DW. Ischemia-induced neuronal apoptosis. Curr Opin Neurobiol 1996; 6: 667–672.

    Google Scholar 

  2. Linnik MD. Role of apoptosis in acute neurodegenerative disorders. Restor Neurol Neurosci 1996; 9: 219–225.

    Google Scholar 

  3. Stefanis L, Burke RE, Greene LA. Apoptosis in neurodegenerative disorders. Curr Opin Neurol 1997; 10: 299–305.

    Google Scholar 

  4. Mazarakis ND, Edwards AD, Mehmet H. Apoptosis in neural development and disease. Arch Dis Childhood 1997; 77: F165– F170.

    Google Scholar 

  5. Savitz SI, Rosenbaum DM. Apoptosis in neurological disease. Neurosurgery 1998; 42: 555–572.

    Google Scholar 

  6. Yuan J, Shaham S, Ledoux S, Ellis HM, Horvitz HR. The C. elegans cell death gene ced-3 encodes a protein similar to mammalian interleukin-1β-converting enzyme. Cell 1993; 75: 641–652.

    Google Scholar 

  7. Alnemri ES, Livingston DJ, Nicholson DW, et al. Human ICE/ced-3 protease nomenclature. Cell 1996; 87: 171.

    Google Scholar 

  8. Salvesen GS, Dixit VM. Caspases: Intracellular signaling by proteases. Cell 1997; 91: 443–446.

    Google Scholar 

  9. Deshmukh M, Vasilakos J, Deckwerth TL, et al. Genetic and metabolic status of NGF-deprived sympathetic neurons saved by an inhibitor of ICE-family proteases. J Cell Biol 1996; 135: 1341–1354.

    Google Scholar 

  10. McCarthy MJ, Rubin LL, Philpott KL. Involvement of caspases in sympathetic neuron apoptosis. J Cell Sci 1997; 110: 2165– 2173.

    Google Scholar 

  11. Stefanis L, Park DS, Yan CYI, et al. Induction of CPP32-like activity in PC12 cells by withdrawal of trophic support- dissociation from apoptosis. J Biol Chem 1996; 271: 30663– 30671.

    Google Scholar 

  12. Schulz JB, Weller M, Klockgether T. Potassium deprivation-induced apoptosis of cerebellar granule neurons-a sequential requirement for new mRNA and protein synthesis, ICE-like protease activity, and reactive oxygen species. J Neurosci 1996; 16: 4696–4706.

    Google Scholar 

  13. Armstrong RC, Aja TJ, Hoang KD, et al. Activation of the CED3/ICE-related protease CPP32 in cerebellar granule neurons undergoing apoptosis but not necrosis. J Neurosci 1997; 17: 553–562.

    Google Scholar 

  14. Miller TM, Moulder KL, Knudson CM, et al. Bax deletion further orders the cell death pathway in cerebellar granule cells and suggests a caspase-independent pathway to cell death. J Cell Biol 1997; 139: 205–217.

    Google Scholar 

  15. Eldadah BA, Yakovlev AG, Faden AI. The role of CED-3-related cysteine proteases in apoptosis of cerebellar granule cells. J Neurosci 1997; 17: 6105–6113.

    Google Scholar 

  16. Keane RW, Srinivasan A, Foster LM, et al. Activation of CPP32 during apoptosis of neurons and astrocytes. J Neurosci Res 1997; 48: 168–180.

    Google Scholar 

  17. Gagliardini V, Fernandez PA, Lee RK, et al. Prevention of vertebrate neuronal death by the crmA gene. Science 1994; 263: 826–828.

    Google Scholar 

  18. Martinou I, Fernandez PA, Missotten M, et al. Viral proteins E1B19K and p35 protect sympathetic neurons from cell death induced by NGF deprivation. J Cell Biol 1995; 128: 201–208.

    Google Scholar 

  19. Milligan CE, Prevette D, Yaginuma H, et al. Peptide inhibitors of the ICE protease family arrest programmed cell death of motoneurons in vivo and in vitro. Neuron 1995; 15: 385–393.

    Google Scholar 

  20. Troy CM, Stefanis L, Prochiantz A, Greene LA, Shelanski ML. The contrasting roles of ICE family proteases and interleukin-1β in apoptosis induced by trophic factor withdrawal and by copper/zinc superoxide dismutase down-regulation. Proc Natl Acad Sci USA 1996; 93: 5635–5640.

    Google Scholar 

  21. Taylor J, Gatchalian CL, Keen G, Rubin LL. Apoptosis in cerebellar granule neurones-involvement of interleukin-1-beta converting enzyme-like proteases. J Neurochem 1997; 68: 1598–1605.

    Google Scholar 

  22. Tanabe H, Eguchi Y, Shimizu S, Martinou JC, Tsujimoto Y. Death-signalling cascade in mouse cerebellar granule neurons. Eur J Neurosci 1998; 10: 1403–1411.

    Google Scholar 

  23. D'mello SR, Aglieco F, Roberts MR, Borodezt K, Haycock JW. A DEVD-inhibited caspase other than cpp32 is involved in the commitment of cerebellar granule neurons to apoptosis induced by k+ deprivation. J Neurochem 1998; 70: 1809–1818.

    Google Scholar 

  24. Gottron FJ, Ying HS, Choi DW. Caspase inhibition selectively reduces the apoptotic component of oxygen-glucose deprivation-induced cortical neuronal cell death. Mol Cell Neurosci 1997; 9: 159–169.

    Google Scholar 

  25. Kuida K, Zheng TS, Na SQ, et al. Decreased apoptosis in the brain and premature lethality in CPP32-deficient mice. Nature 1996; 384: 368–372.

    Google Scholar 

  26. Choi DW. Excitotoxic cell death. J Neurobiol 1992; 23: 1261– 1276.

    Google Scholar 

  27. Kirino T. Delayed neuronal death in the gerbil hippocampus following ischemia. Brain Res 1982; 239: 57–69.

    Google Scholar 

  28. Pulsinelli WA, Brierley JB, Plum F. Temporal profile of neuronal damage in a model of transient forebrain ischemia. Annals Neurol 1982; 11: 491–498.

    Google Scholar 

  29. Du C, Hu R, Csernansky CA, Hsu CY, Choi DW. Very delayed infarction after mild focal cerebral ischemia: a role for apoptosis? J Cereb Blood Flow Metab 1996; 16: 195–201.

    Google Scholar 

  30. Goto K, Ishige A, Sekiguchi K, et al. Effects of cycloheximide on delayed neuronal death in rat hippocampus. Brain Res 1990; 534: 299–302.

    Google Scholar 

  31. Shigeno T, Yamasaki Y, Kato G, et al. Reduction of delayed neuronal death by inhibition of protein synthesis. Neurosci Lett 1990; 120: 117–119.

    Google Scholar 

  32. Loddick SA, MacKenzie A, Rothwell NJ. An ICE inhibitor, z-VAD-DCB attenuates ischaemic brain damage in the rat. Neuroreport 1996; 7: 1465–1468.

    Google Scholar 

  33. Hara H, Friedlander RM, Gagliardini V, et al. Inhibition of interleukin-1beta converting enzyme family proteases reduces ischaemic and excitotoxic neuronal damage. Proc Natl Acad Sci USA 1997; 94: 2007–2012.

    Google Scholar 

  34. Friedlander RM, Gagliardini V, Hara H, et al. Expression of a dominant negative mutant of interleukin-1 beta converting enzyme in transgenic mice prevents neuronal cell death induced by trophic factor withdrawal and ischaemic brain injury. J Exp Med 1997; 185: 933–940.

    Google Scholar 

  35. Schielke GP, Yang GY, Shivers BD, Betz AL. Reduced ischaemic brain injury in interleukin-1 beta converting enzymedeficient mice. J Cereb Blood Flow Metab 1998; 18: 180–185.

    Google Scholar 

  36. Chen J, Nagayama T, Jin KL, et al. Induction of caspase-3-like protease may mediate delayed neuronal death in the hippocampus after transient cerebral ischemia. J Neurosci 1998; 18: 4914–4928.

    Google Scholar 

  37. Himi T, Ishizaki Y, Murota S. A caspase inhibitor blocks ischaemia-induced delayed neuronal death in the gerbil. Eur J Neurosci 1998; 10: 777–781.

    Google Scholar 

  38. Cheng Y, Deshmukh M, D'Costa A, et al. Caspase inhibitor affords neuroprotection with delayed administration in a rat model of neonatal hypoxic-ischaemic brain injury. J Clin Invest 1998; 101: 1992–1999.

    Google Scholar 

  39. Namura S, Zhu JM, Fink K, et al. Activation and cleavage of caspase-3 in apoptosis induced by experimental cerebral ischemia. J Neurosci 1998; 18: 3659–3668.

    Google Scholar 

  40. Rothwell NJ, Loddick SA, Stroemer P. Interleukins and cerebral ischaemia. Int Rev Neurobiol 1997; 40: 281–298.

    Google Scholar 

  41. Ni B, Wu X, Su Y, et al. Transient global forebrain ischemia induces a prolonged expression of the caspase-3 mRNA in rat hippocampal CA1 pyramidal neurons. J Cereb Blood Flow Metab 1998; 18: 248–256.

    Google Scholar 

  42. Kaushal GP, Singh AB, Shah SV. Identification of gene family of caspases in rat kidney and altered expression in ischemia-reperfusion injury. Am J Physiology 1998; 274: F587–F595.

    Google Scholar 

  43. Endres M, Namura S, Shimizu SM, 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.

    Google Scholar 

  44. Hara H, Fink K, Endres M, et al. Attenuation of transient focal cerebral ischaemic injury in transgenic mice expressing a mutant ICE inhibitory protein. J Cereb Blood Flow Metab 1997; 17: 370–375.

    Google Scholar 

  45. Relton JK, Rothwell NJ. Interleukin-1 receptor antagonist inhibits ischaemic and excitotoxic neuronal damage in the rat. Brain Res Bull 1992; 29: 243–246.

    Google Scholar 

  46. Yamasaki Y, Matsuura N, Shozuhara H, et al. Interleukin-1 as a pathogenetic mediator of ischaemic brain damage in rats. Stroke 1995; 26: 676–680.

    Google Scholar 

  47. Yakovlev AG, Knoblach SM, Fan L, et al. Activation of CPP32-like caspases contributes to neuronal apoptosis and neurological dysfunction after traumatic brain injury. J Neurosci 1997; 17: 7415–7424.

    Google Scholar 

  48. Ma JY, Endres M, Moskowitz MA. Synergistic effects of caspase inhibitors and MK-801 in brain injury after transient focal cerebral ischaemia in mice. Br J Pharmacol 1998; 124: 756– 762.

    Google Scholar 

  49. Charriaut MC, Ben AY. A cautionary note on the use of the TUNEL stain to determine apoptosis. Neuroreport 1995; 7: 61– 64.

    Google Scholar 

  50. Thomas LB, Gates DJ, Richfield EK, et al. DNA end labeling (TUNEL) in Huntington's disease and other neuropathological conditions. Exp Neurol 1995; 133: 265–272.

    Google Scholar 

  51. Su JH, Anderson AJ, Cummings BJ, Cotman CW. Immunohistochemical evidence for apoptosis in Alzheimer's disease. Neuroreport 1994; 5: 2529–2533.

    Google Scholar 

  52. Lassmann H, Bancher C, Breitschopf H, et al. Cell death in Alzheimer's disease evaluated by DNA fragmentation in situ. Acta Neuropathologica 1995; 89: 35–41.

    Google Scholar 

  53. Dragunow M, Faull RL, Lawlor P, et al. In situ evidence for DNA fragmentation in Huntington's disease striatum and Alzheimer's disease temporal lobes. Neuroreport 1995; 6: 1053– 1057.

    Google Scholar 

  54. Smale G, Nichols NR, Brady DR, Finch CE, Horton WJ. Evidence for apoptotic cell death in Alzheimer's disease. Exp Neurol 1995; 133: 225–230.

    Google Scholar 

  55. Li WP, Chan WY, Lai HW, Yew DT. Terminal dUTP nick end labeling (TUNEL) positive cells in the different regions of the brain in normal aging and Alzheimer patients. J Mol Neurosci 1997; 8: 75–82.

    Google Scholar 

  56. Migheli A, Cavalla P, Marino S, Schiffer D. A study of apoptosis in normal and pathologic nervous tissue after in situ end labeling of DNA strand breaks. J Neuropath Exp Neurol 1994; 53: 606–616.

    Google Scholar 

  57. Kosel S, Egensperger R, von Eitzen U, Mehraein P, Graeber MB. On the question of apoptosis in the parkinsonian substantia nigra. Acta Neuropathologica 1997; 93: 105–108.

    Google Scholar 

  58. Tompkins MM, Basgall EJ, Zamrini E, Hill WD. Apoptoticlike changes in Lewy-body-associated disorders and normal aging in substantia nigral neurons. Am J Pathology 1997; 150: 119–131.

    Google Scholar 

  59. 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: 3775–3787.

    Google Scholar 

  60. Wellington CL, Brinkman RR, O'Kusky JR, Hayden MR. Toward understanding the molecular pathology of Huntington's disease. Brain Pathol 1997; 7: 979–1002.

    Google Scholar 

  61. Kim TW, Pettingell WH, Jung YK, Kovacs DM, Tanzi RE. Alternative cleavage of Alzheimer-associated presenilins during apoptosis by a caspase-3 family protease. Science 1997; 277: 373–376.

    Google Scholar 

  62. Goldberg YP, Nicholson DW, Rasper DM, et al. Cleavage of huntingtin by apopain, a proapoptotic cysteine protease, is modulated by the polyglutamine tract. Nat Genetics 1996; 13: 442–449.

    Google Scholar 

  63. Miyashita T, Okamuraoho Y, Mito Y, Nagafuchi S, Yamada M. Dentatorubral pallidoluysian atrophy (DRPLA) protein is cleaved by caspase-3 during apoptosis. J Biol Chem 1997; 272: 29238–29242.

    Google Scholar 

  64. Wellington CL, Ellerby LM, Hackam AS, et al. Caspase cleavage of gene products associated with triplet expansion disorders generates truncated fragments containing the polyglutamine tract. J Biol Chem 1998; 273: 9158–9167.

    Google Scholar 

  65. Warrick JM, Paulson HL, Grayboard GL, et al. Expanded polyglutamine protein forms nuclear inclusions and causes neural degeneration in Drosophila. Cell 1998; 93: 939–949.

    Google Scholar 

  66. Loetscher H, Deuschle U, Brockhaus M, et al. Presenilins are processed by caspase-type proteases. J Biol Chem 1997; 272: 20655–20659.

    Google Scholar 

  67. Vito P, Ghayur T, D'Adamio L. Generation of anti-apoptotic presenilin-2 polypeptides by alternative transcription, proteolysis, and caspase-3 cleavage. J Biol Chem 1997; 272: 28315– 28320.

    Google Scholar 

  68. Brockhaus M, Grunberg J, Rohrig S, et al. Caspase-mediated cleavage is not required for the activity of presenilins in amyloidogenesis and notch signaling. Neuroreport 1998; 9: 1481– 1486.

    Google Scholar 

  69. Yang F, Sun X, Beech W, et al. Antibody to caspase-cleaved actin detects apoptosis in differentiated neuroblastoma and plaque-associated neurons and microglia in Alzheimer's disease. Am J Pathology 1998; 152: 379–389.

    Google Scholar 

  70. Durham HD, Roy J, Dong L, Figlewicz DA. Aggregation of mutant Cu/Zn superoxide dismutase proteins in a culture model of ALS. J Neuropath Exp Neurol 1997; 56: 523– 530.

    Google Scholar 

  71. Ghadge GD, Lee JP, Bindokas VP, et al. Mutant super-oxide dismutase-1-linked familial amyotrophic lateral sclerosis: molecular mechanisms of neuronal death and protection. J Neurosci 1997; 17: 8756–8766.

    Google Scholar 

  72. Gurney ME, Pu H, Chiu AY, et al. Motor neuron degeneration in mice that express a human Cu,Zn superoxide dismutase mutation. Science 1994; 264: 1772–1775.

    Google Scholar 

  73. Friedlander RM, Brown RH, Gagliardini V, Wang J, Yuan J. Inhibition of ICE slows ALS in mice. Nature 1997; 388: 31.

    Google Scholar 

  74. Papermaster DS. Apoptosis of the mammalian retina and lens. Cell Death Differen 1997; 4: 21–28.

    Google Scholar 

  75. Davidson FF, Steller H. Blocking apoptosis prevents blindness in Drosophila retinal degeneration mutants. Nature 1998; 391: 587–591.

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Molecular Biology and Pharmacology, Washington University School of Medicine, 660 South Euclid Avenue, St. Louis, MO, 63110-1031, USA

    M. Deshmukh

Authors
  1. M. Deshmukh
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Deshmukh, M. Caspases in ischaemic brain injury and neurodegenerative disease. Apoptosis 3, 387–394 (1998). https://doi.org/10.1023/A:1009602401251

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1023/A:1009602401251

Search

Navigation