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. 2006 Apr 5;11(4):422–431. doi: 10.1111/j.1750-3639.2001.tb00410.x

Expression of Death‐related Proteins in Dentate Granule Cells in Human Bacterial Meningitis

Joachim Gerber 1, Wolfgang Brück 2, Christine Stadelmann 2, Stefanie Bunkowski 1, Hans Lassmann 3, Roland Nau 1,
PMCID: PMC8098385  PMID: 11556687

Abstract

Neuronal apoptosis in the dentate gyrus has been observed in animal models of bacterial meningitis and in humans dying in the course of the disease. To evaluate the mechanisms of neuronal cell death, hippocampal sections of 20 patients dying from bacterial meningitis were investigated by immunohistochemistry using antibodies against the proform of caspase‐3 and the active enzyme, bcl‐2, bax and p53. In the dentate granule cell layer, the median density of neurons with an apoptotic morphology was 7.6/mm2 (0–15.6/mm2). The median density of immunoreactive neurons was 2.3/mm2 (procaspase‐3), 0.9/mm2 (activated caspase‐3), 1.8/mm2 (bcl‐2), 1.1/mm2 (bax) and 0.4/mm2 (p53). 80% of neurons immunoreactive for active caspase‐3 had an apoptotic morphology, whereas only 10% of all procaspase‐3 stained neurons showed signs of apoptosis. Apoptotic cell death is present in humans dying in the course of bacterial meningitis in the dentate gyrus of the Formatio hippocampi. Neuronal expression of caspase‐3, bcl‐2 and bax suggests an involvement of these proteins in neuronal death.

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References

  • 1. Armstrong RC, Aja T, Xiang J, Gaur S, Krebs JF, Hoang K, Bai X, Korsmeyer SJ, Karanewsky DS, Fritz LC, Tomaselli KJ (1996) Fas‐induced activation of the cell death‐related protease CPP32 is inhibited by bcl‐2 and ICE family protease inhibitors. J Biol Chem 271: 850–855. [DOI] [PubMed] [Google Scholar]
  • 2. Banasiak KJ, Haddad GG (1998) Hypoxia‐induced apoptosis: effect of hypoxic severity and role of p53 in neuronal death. Brain Res 797: 295–304. [DOI] [PubMed] [Google Scholar]
  • 3. Bonfoco E, Krainc D, Ankarcrona M, Nicotera P, Lipton SA (1995) Apoptosis and necrosis: two distinct events induced, respectively, by mild and intense insults with N‐methyl‐ D aspartate or nitric oxide/superoxide in cortical cell cultures. Proc Natl Acad Sci USA 92: 7162–7166. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 4. Borner C, Monney L (1999) Apoptosis without caspases: an inefficient molecular guillotine Cell Death Differ 6: 497–507. [DOI] [PubMed] [Google Scholar]
  • 5. Braun JS, Novak R, Herzog KH, Bodner SM, Cleveland JL, Tuomanen EI (1999) Neuroprotection by a caspase inhibitor in acute bacterial meningitis. Nature Med 5: 298–302. [DOI] [PubMed] [Google Scholar]
  • 6. Brück Y, Brück W, Kretzschmar H, Lassmann H (1996) Evidence for neuronal apoptosis in pontosubicular neuronal necrosis. Neuropathol Appl Neurobiol 22: 23–29. [PubMed] [Google Scholar]
  • 7. Chen J, Nagayama T, Jin K, Stetler A, Zhu RL, Graham SH, Simon RP (1998) Induction of caspase‐3‐like protease may mediate delayed neuronal death in the hippocampus after transient cerebral ischemia. J Neurosci 18: 4914–4928. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 8. Chen J, Zhu RL, Nakayama M, Kawaguchi K, Jin K, Stetler RA, Simon RP, Graham SH (1996) Expression of the apoptosis‐effector gene, bax, is up‐regulated in vulnerable hippocampal CA1 neurons following global ischemia. J Neurochem 67: 64–71. [DOI] [PubMed] [Google Scholar]
  • 9. Chinnaiyan AM, Orth K, O'Rourke K, Duan H, Poirier GG, Dixit VM (1996) Molecular ordering of the cell death pathway. bcl‐2 and bcl‐xL function upstream of the CED‐3‐like apoptotic proteases. J Biol Chem 271: 4573–4576. [DOI] [PubMed] [Google Scholar]
  • 10. Clark RSB, Chen J, Watkins SC, Kochanek PM, Chen M, Stetler RA, Loeffert JE, Graham SH (1997) Apoptosissuppressor gene bcl‐2 expression after traumatic brain injury in rats. J Neurosci 17: 9172–9182. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 11. Conrad CD, Roy EJ (1995) Dentate gyrus destruction and spatial learning impairment after corticosteroid removal in young and middle‐aged rats. Hippocampus 5: 1–15. [DOI] [PubMed] [Google Scholar]
  • 12. Durand ML, Calderwood SB, Weber DJ, Miller SI, Southwick FS, Caviness VS, Swartz MN (1993) Acute bacterial meningitis in adults. A review of 493 episodes. New Engl J Med 328: 21–28. [DOI] [PubMed] [Google Scholar]
  • 13. Edwards MS, Rench MA, Haffar AAM, Murphy MA, Desmond MM, Bader CJ (1985) Long‐term‐sequelae of group B streptococcal meningitis in infants. J Pediatr 106: 717–722. [DOI] [PubMed] [Google Scholar]
  • 14. Eriksson PS, Perfilieva E, Björk‐Eriksson T, Alborn A, Nordborg C, Peterson DA, Gage FH (1998) Neurogenesis in the adult human hippocampus. Nature Med 4: 1313–1317. [DOI] [PubMed] [Google Scholar]
  • 15. Ferrer I, López E, Blanco R, Rivera R, Ballabriga J, Pozas E, Martí E (1998) Bcl‐2, bax, and bcl‐x expression in the CA1 area of the hippocampus following transient forebrain ischemia in the adult gerbil. Exp Brain Res 121: 167–173. [DOI] [PubMed] [Google Scholar]
  • 16. Ferrer I, Pozas E, López E, Ballabriga J (1997) Bcl‐2, bax, and bcl‐x expression following hypoxia‐ischemia in the infant rat brain. Acta Neuropathol 94: 583–589. [DOI] [PubMed] [Google Scholar]
  • 17. Gerber J, Raivich G, Wellmer A, Noeske C, Kunst T, Werner A, Brück W, Nau R (2001) A mouse model of Streptococcus pneumoniae meningitis mimicking several features of human disease. Acta Neuropathol 101: 499–508. [DOI] [PubMed] [Google Scholar]
  • 18. Hicks RR, Smith DH, Lowenstein DH, Saint Marie R, McIntosh TK (1993) Mild experimental brain injury in the rat induces cognitive deficits associated with regional neuronal loss in the hippocampus. J Neurotrauma 10: 405–414. [DOI] [PubMed] [Google Scholar]
  • 19. Hockenberry D, Núñez G, Milliman C, Schreiber RD, Korsmeyer SJ (1990) Bcl‐2 is an inner mitochondrial membrane protein that blocks programmed cell death. Nature 348: 334–336. [DOI] [PubMed] [Google Scholar]
  • 20. Hollstein M, Sidransky D, Vogelstein B, Harris CC (1991) p53 mutations in human cancers. Science 253: 49–53. [DOI] [PubMed] [Google Scholar]
  • 21. Isenmann S, Stoll G, Schröter M, Krajewski S, Reed JC, Bähr M (1998) Differential regulation of bax, bcl‐2 and bcl‐X proteins in focal cortical ischemia in the rat. Brain Pathol 8: 49–62. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 22. Knudson CM, Korsmeyer SJ (1997) Bcl‐2 and bax function independently to regulate cell death. Nature Genet 16: 358–363. [DOI] [PubMed] [Google Scholar]
  • 23. Krajewska M, Wang HG, Krajewski S, Zapata JM, Shabaik A, Gascoyne R, Reed JC (1997) Immunohistochemical analysis of in vivo patterns of expression of CPP32 (caspase‐3), a cell death protease. Cancer Res 57: 1605–1613. [PubMed] [Google Scholar]
  • 24. Leib SL, Kim YS, Chow LL, Sheldon RA, Täuber MG (1996) Reactive oxygen intermediates contribute to necrotic and apoptotic cell death in an infant rat model of bacterial meningitis due to group B streptococci. J Clin Invest 98: 2632–2639. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 25. Lemaire C, Andreau K, Souvannavong V, Adam A (1998) Inhibition of caspase activity induces a switch from apoptosis to necrosis. FEBS Lett 425: 266–270. [DOI] [PubMed] [Google Scholar]
  • 26. Loeffler JM, Ringer R, Hablutzel M, Täuber MG, Leib SL (2001) The free radical scavenger alpha‐phenyl‐tert‐butyl nitrone aggravates hippocampal apoptosis and learning deficits in experimental pneumococcal meningitis. J Infect Dis 183: 247–252. [DOI] [PubMed] [Google Scholar]
  • 27. Martin LJ, Al‐Abdulla NA, Brambrink AM, Kirsch JR, Sieber FE, Portera‐Cailliau C (1998) Neurodegeneration in excitotoxicity, global cerebral ischemia, and target deprivation: a perspective on the contributions of apoptosis and necrosis. Brain Res Bull 46: 281–309. [DOI] [PubMed] [Google Scholar]
  • 28. Mercer WE, Shields MT, Amin M, Sauve GJ, Appella E, Romano JW, Ullrich SJ (1990) Negative growth regulation in a glioblastoma tumor cell line that conditionally expresses human wild‐type p53. Proc Natl Acad Sci USA 87: 6166–6170. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 29. Mering M , von Wellmer A , Michel U, Bunkowski S, Tlustochowska A, Brück W, Kuhnt U, Nau R (2001) Transcriptional regulation of caspases in experimental pneumococcal meningitis. Brain Pathol 11: 282–295. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 30. Miller TM, Moulder KL, Knudson CM, Creedon DJ, Deshmukh M, Korsmeyer SJ, Johnson EM (1997) Bax deletion further orders the cell death pathway in cerebellar granule cells and suggests a caspase‐independent pathway to cell death. J Cell Biol 139: 205–217. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 31. Mishkin M, Vargha‐Khadem F, Gadian DG (1998) Amnesia and the organization of the hippocampal system. Hippocampus 8: 212–216. [DOI] [PubMed] [Google Scholar]
  • 32. Miyashita T, Harigai M, Hanada M, Reed JC (1994) Identification of a p53‐dependent negative response element in the bcl‐2 gene. Cancer Res 54: 3131–3135. [PubMed] [Google Scholar]
  • 33. Miyashita T, Reed JC (1995) Tumor suppressor p53 is a direct transcriptional activator of the human bax gene. Cell 80: 293–299. [DOI] [PubMed] [Google Scholar]
  • 34. Namura S, Zhu J, Fink K, Endres M, Srinivasan A, Tomaselli KJ, Yuan J, Moskowitz MA (1998) Activation and cleavage of caspase‐3 in apoptosis induced by experimental cerebral ischemia. J Neurosci 18: 3659–3668. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 35. Nau R, Soto A, Brück W (1999) Apoptosis of neurons in the dentate gyrus in humans suffering from bacterial meningitis. J Neuropathol Exp Neurol 58: 265–274. [DOI] [PubMed] [Google Scholar]
  • 36. Nelson A, Lebessi A, Sowinski P, Hodges H (1997) Comparison of effects on global cerebral ischemia on spatial learning in the standard and radial water maze: relationship of hippocampal damage to performance. Behav Brain Res 85: 93–116. [DOI] [PubMed] [Google Scholar]
  • 37. Nicholson DW, Thornberry NA (1997) Caspases: killer proteases. TIBS 22: 299–306. [DOI] [PubMed] [Google Scholar]
  • 38. Oltvai ZN, Milliman CL, Korsmeyer SJ (1993) Bcl‐2 heterodimerizes in vivo with a conserved homolog, bax, that accelerates programmed cell death. Cell 74: 609–619. [DOI] [PubMed] [Google Scholar]
  • 39. Stadelmann C, Mews I, Srinivasan A, Deckwerth TL, Lassmann H, Brück W (2001) Expression of cell deathassociated proteins in neuronal apoptosis associated with pontosubicular neuron necrosis. Brain Pathol 11: 273–281. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 40. Taylor HG, Michaels RH, Mazur PM, Bauer R, Liden CB (1984) Intellectual, neuropsychological and achievement outcomes in children six to eight years after recovery from Haemophilus influenzae meningitis. Pediatr 74: 198–205. [PubMed] [Google Scholar]
  • 41. Wellmer A, Noeske C, Gerber J, Munzel U, Nau R (2000) Spatial memory and learning deficits after experimental pneumococcal meningitis in mice. Neurosci Lett 296: 137–140. [DOI] [PubMed] [Google Scholar]
  • 42. Wenger JD, Allen WH, Facklam RR, Gaventa S, Broome CV (1990) Bacterial meningitis in the United States, 1986: Report of a multistate surveillance study. J Infect Dis 162: 1316–1323. [DOI] [PubMed] [Google Scholar]
  • 43. Yonish‐Rouach E, Resnitzky D, Lotem J, Sachs L, Kimchi A, Oren M (1991) Wild type p53 induces apoptosis of myeloid leukaemic cells that is inhibited by interleukin‐6. Nature 352: 345–347. [DOI] [PubMed] [Google Scholar]
  • 44. Zysk G, Brück W, Gerber J, Brück Y, Prange HW, Nau R (1996) Antiinflammatory treatment influences neuronal apoptotic cell death in the dentate gyrus in experimental pneumococcal meningitis. J Neuropathol Exp Neurol 55: 722–728. [DOI] [PubMed] [Google Scholar]

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