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PMID: 12019321 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S.

Caspase cascades in human immunodeficiency virus-associated neurodegeneration.

The Journal of neuroscience : the official journal of the Society for Neuroscience ·Vol. 22 ·No. 10 ·2002-05-15 ·Pages 4015-24

Garden GA, Budd SL, Tsai E, Hanson L, Kaul M, D'Emilia DM, Friedlander RM, Yuan J, Masliah E, Lipton SA

Abstract

Many patients infected with human immunodeficiency virus-1 (HIV-1) develop a syndrome of neurologic deterioration known as HIV-associated dementia (HAD). Neurons are not productively infected by HIV-1; thus, the mechanism of HIV-induced neuronal injury remains incompletely understood. Several investigators have observed evidence of neuronal injury, including dendritic degeneration, and apoptosis in CNS tissue from patients with HAD. Caspase enzymes, proteases associated with the process of apoptosis, are synthesized as inactive proenzymes and are activated in a proteolytic cascade after exposure to apoptotic signals. Here we demonstrate that HAD is associated with active caspase-3-like immunoreactivity that is localized to the soma and dendrites of neurons in affected regions of the human brain. Additionally, the cascade of caspase activation was studied using an in vitro model of HIV-induced neuronal apoptosis. Increased caspase-3 proteolytic activity and mitochondrial release of cytochrome c were observed in cerebrocortical cultures exposed to the HIV coat protein gp120. Specific inhibitors of both the Fas/tumor necrosis factor-alpha/death receptor pathway and the mitochondrial caspase pathway prevented gp120-induced neuronal apoptosis. Caspase inhibition also prevented the dendrite degeneration observed in vivo in transgenic mice with CNS expression of HIV/gp120. These findings suggest that pharmacologic interventions aimed at the caspase enzyme pathways may be beneficial for the prevention or treatment of HAD.

MeSH Terms
AIDS Dementia Complex/enzymology Adult Animals Apoptosis/drug effects Astrocytes/cytology,drug effects Brain/enzymology,pathology Caspase 1/genetics Caspase 3 Caspase 8 Caspase 9 Caspase Inhibitors Caspases/metabolism Cells, Cultured Cytochrome c Group/metabolism Dendrites/enzymology Enzyme Activation/drug effects Enzyme Inhibitors/pharmacology HIV Envelope Protein gp120/genetics,toxicity Humans Mice Mice, Transgenic Microglia/cytology,drug effects Middle Aged Neurons/cytology,drug effects,enzymology Prospective Studies Tumor Necrosis Factor-alpha/antagonists & inhibitors fas Receptor/drug effects
Chemicals
Caspase Inhibitors Cytochrome c Group Enzyme Inhibitors HIV Envelope Protein gp120 Tumor Necrosis Factor-alpha fas Receptor CASP3 protein, human CASP8 protein, human CASP9 protein, human Casp3 protein, mouse Casp8 protein, mouse Casp9 protein, mouse Caspase 3 Caspase 8 Caspase 9 Caspases Caspase 1
Authors & Affiliations
10 authors, click to expand affiliations / ORCID
Garden Gwenn A
Department of Neurology, University of Washington, Seattle, Washington 98195, USA. gagarden@u.washington.edu
Budd Samantha L
Tsai Elena
Hanson Lisa
Kaul Marcus
D'Emilia Danielle M
Friedlander Robert M
Yuan Junying
Masliah Eliezer
Lipton Stuart A
References (71)
71 references, click to expand
  1. HIV-1 Tat induces neuronal death via tumor necrosis factor-alpha and activation of non-N-methyl-D-aspartate receptors by a NFkappaB-independent mechanism.
    J Biol Chem. 1998 Jul 10;273(28):17852-8 PMID: 9651389
  2. Neuronal apoptosis does not correlate with dementia in HIV infection but is related to microglial activation and axonal damage.
    Neuropathol Appl Neurobiol. 1999 Apr;25(2):123-33 PMID: 10216000
  3. Inhibition of caspase-1 slows disease progression in a mouse model of Huntington's disease.
    Nature. 1999 May 20;399(6733):263-7 PMID: 10353249
  4. Pathogenesis of HIV-1 associated neurodegeneration.
    Crit Rev Neurobiol. 1996;10(1):57-67 PMID: 8853954
  5. Dementia in AIDS patients: incidence and risk factors. Multicenter AIDS Cohort Study.
    Neurology. 1993 Nov;43(11):2245-52 PMID: 8232937
  6. DNA damage and activated caspase-3 expression in neurons and astrocytes: evidence for apoptosis in frontotemporal dementia.
    Exp Neurol. 2000 May;163(1):9-19 PMID: 10785439
  7. Rescue from death but not from functional impairment: caspase inhibition protects dopaminergic cells against 6-hydroxydopamine-induced apoptosis but not against the loss of their terminals.
    J Neurochem. 2001 Apr;77(1):263-73 PMID: 11279282
  8. Evidence that Wallerian degeneration and localized axon degeneration induced by local neurotrophin deprivation do not involve caspases.
    J Neurosci. 2000 Feb 15;20(4):1333-41 PMID: 10662823
  9. Evidence that increases of mitochondrial immunoreactive IL-1beta by HIV-1 gp120 implicate in situ cleavage of pro-IL-1beta in the neocortex of rat.
    J Neurochem. 2001 Aug;78(3):611-8 PMID: 11483664
  10. Secretion of neurotoxins by mononuclear phagocytes infected with HIV-1.
    Science. 1990 Dec 14;250(4987):1593-6 PMID: 2148832
  11. Bid, a Bcl2 interacting protein, mediates cytochrome c release from mitochondria in response to activation of cell surface death receptors.
    Cell. 1998 Aug 21;94(4):481-90 PMID: 9727491
  12. Inhibition of HIV-1 gp120-induced apoptosis in neuroblastoma SK-N-SH cells by an antisense oligodeoxynucleotide against p53.
    AIDS. 1998 Mar 5;12(4):349-54 PMID: 9520163
  13. Uptake of HIV-1 tat protein mediated by low-density lipoprotein receptor-related protein disrupts the neuronal metabolic balance of the receptor ligands.
    Nat Med. 2000 Dec;6(12):1380-7 PMID: 11100124
  14. Differential modulation of cell death proteins in human brain cells by tumor necrosis factor alpha and platelet activating factor.
    J Neurosci Res. 1998 Nov 15;54(4):530-8 PMID: 9822163
  15. Involvement of activated caspase-3-like proteases in N-methyl-D-aspartate-induced apoptosis in cerebrocortical neurons.
    J Neurochem. 2000 Jan;74(1):134-42 PMID: 10617114
  16. Central nervous system damage produced by expression of the HIV-1 coat protein gp120 in transgenic mice.
    Nature. 1994 Jan 13;367(6459):188-93 PMID: 8114918
  17. The envelope glycoprotein of human immunodeficiency virus type 1 stimulates release of neurotoxins from monocytes.
    Proc Natl Acad Sci U S A. 1993 Apr 1;90(7):2769-73 PMID: 8464887
  18. Intracellular CXCR4 signaling, neuronal apoptosis and neuropathogenic mechanisms of HIV-1-associated dementia.
    J Neuroimmunol. 1999 Aug 3;98(2):185-200 PMID: 10430052
  19. CXCR4-activated astrocyte glutamate release via TNFalpha: amplification by microglia triggers neurotoxicity.
    Nat Neurosci. 2001 Jul;4(7):702-10 PMID: 11426226
  20. Functional role and therapeutic implications of neuronal caspase-1 and -3 in a mouse model of traumatic spinal cord injury.
    Neuroscience. 2000;99(2):333-42 PMID: 10938439
  21. Delayed mitochondrial dysfunction in excitotoxic neuron death: cytochrome c release and a secondary increase in superoxide production.
    J Neurosci. 2000 Aug 1;20(15):5715-23 PMID: 10908611
  22. Human immunodeficiency virus type 1 Tat induces apoptosis and increases sensitivity to apoptotic signals by up-regulating FLICE/caspase-8.
    J Virol. 1999 Mar;73(3):1956-63 PMID: 9971775
  23. Evidence of apoptotic cell death in HIV encephalitis.
    Am J Pathol. 1995 May;146(5):1121-30 PMID: 7747806
  24. Caspases - controlling intracellular signals by protease zymogen activation.
    Biochim Biophys Acta. 2000 Mar 7;1477(1-2):299-306 PMID: 10708865
  25. Human brain-cell death induced by tumour-necrosis-factor-related apoptosis-inducing ligand (TRAIL)
    Lancet. 2000 Sep 2;356(9232):827-8 PMID: 11022932
  26. Activation and cleavage of caspase-3 in apoptosis induced by experimental cerebral ischemia.
    J Neurosci. 1998 May 15;18(10):3659-68 PMID: 9570797
  27. Chemokines and activated macrophages in HIV gp120-induced neuronal apoptosis.
    Proc Natl Acad Sci U S A. 1999 Jul 6;96(14):8212-6 PMID: 10393974
  28. L-cysteine, a bicarbonate-sensitive endogenous excitotoxin.
    Science. 1990 May 4;248(4955):596-9 PMID: 2185543
  29. Malonate and 3-nitropropionic acid neurotoxicity are reduced in transgenic mice expressing a caspase-1 dominant-negative mutant.
    J Neurochem. 2000 Aug;75(2):847-52 PMID: 10899963
  30. Caspase-3: A vulnerability factor and final effector in apoptotic death of dopaminergic neurons in Parkinson's disease.
    Proc Natl Acad Sci U S A. 2000 Mar 14;97(6):2875-80 PMID: 10688892
  31. Mitochondrial and extramitochondrial apoptotic signaling pathways in cerebrocortical neurons.
    Proc Natl Acad Sci U S A. 2000 May 23;97(11):6161-6 PMID: 10811898
  32. Memantine prevents HIV coat protein-induced neuronal injury in vitro.
    Neurology. 1992 Jul;42(7):1403-5 PMID: 1620355
  33. The CED-4-homologous protein FLASH is involved in Fas-mediated activation of caspase-8 during apoptosis.
    Nature. 1999 Apr 29;398(6730):777-85 PMID: 10235259
  34. Reduction of post-traumatic brain injury and free radical production by inhibition of the caspase-1 cascade.
    Neuroscience. 1999;94(4):1213-8 PMID: 10625061
  35. Macrophage tropism of human immunodeficiency virus type 1 and utilization of the CC-CKR5 coreceptor.
    J Virol. 1997 Feb;71(2):1657-61 PMID: 8995695
  36. Apoptosis induced by infection of primary brain cultures with diverse human immunodeficiency virus type 1 isolates: evidence for a role of the envelope.
    J Virol. 1999 Feb;73(2):897-906 PMID: 9882290
  37. Human immunodeficiency virus type 1 Vpr induces apoptosis in human neuronal cells.
    J Virol. 2000 Oct;74(20):9717-26 PMID: 11000244
  38. 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 ischemic brain injury.
    J Exp Med. 1997 Mar 3;185(5):933-40 PMID: 9120399
  39. Quinolinic acid in cerebrospinal fluid and serum in HIV-1 infection: relationship to clinical and neurological status.
    Ann Neurol. 1991 Feb;29(2):202-9 PMID: 1826418
  40. Apoptosis induced by HIV-1 infection of the central nervous system.
    J Clin Invest. 1996 Nov 1;98(9):1979-90 PMID: 8903316
  41. Study of receptor-mediated neurotoxins released by HIV-1-infected mononuclear phagocytes found in human brain.
    J Neurosci. 1996 May 15;16(10):3139-53 PMID: 8627353
  42. Pathways to neuronal injury and apoptosis in HIV-associated dementia.
    Nature. 2001 Apr 19;410(6831):988-94 PMID: 11309629
  43. HIV-1 protein Tat induces apoptosis of hippocampal neurons by a mechanism involving caspase activation, calcium overload, and oxidative stress.
    Exp Neurol. 1998 Dec;154(2):276-88 PMID: 9878167
  44. Neuronal apoptosis induced by HIV-1 gp120 and the chemokine SDF-1 alpha is mediated by the chemokine receptor CXCR4.
    Curr Biol. 1998 May 7;8(10):595-8 PMID: 9601645
  45. The amino-terminal region of Vpr from human immunodeficiency virus type 1 forms ion channels and kills neurons.
    J Virol. 1999 May;73(5):4230-8 PMID: 10196319
  46. Neuronal cell killing by the envelope protein of HIV and its prevention by vasoactive intestinal peptide.
    Nature. 1988 Oct 13;335(6191):639-42 PMID: 2845276
  47. Recombinant nef HIV-IIIB protein is toxic to human neurons in culture.
    Brain Res. 2000 May 12;864(2):315-26 PMID: 10802040
  48. Cytokine-stimulated, but not HIV-infected, human monocyte-derived macrophages produce neurotoxic levels of l -cysteine.
    J Immunol. 2000 Apr 15;164(8):4265-70 PMID: 10754324
  49. Selective and protracted apoptosis in human primary neurons microinjected with active caspase-3, -6, -7, and -8.
    J Neurosci. 2000 Nov 15;20(22):8384-9 PMID: 11069945
  50. Human immunodeficiency virus type 1 Tat protein induces death by apoptosis in primary human neuron cultures.
    J Neurovirol. 1997 Apr;3(2):168-73 PMID: 9111179
  51. Expression of caspase-3 in brains from paediatric patients with HIV-1 encephalitis.
    Neuropathol Appl Neurobiol. 1999 Oct;25(5):380-6 PMID: 10564527
  52. The HIV envelope protein gp120 is toxic to human brain-cell cultures through the induction of interleukin-6 and tumor necrosis factor-alpha.
    AIDS. 1995 Feb;9(2):137-43 PMID: 7536422
  53. Immunologic NO synthase: elevation in severe AIDS dementia and induction by HIV-1 gp41.
    Science. 1996 Dec 13;274(5294):1917-21 PMID: 8943206
  54. Chemokines regulate hippocampal neuronal signaling and gp120 neurotoxicity.
    Proc Natl Acad Sci U S A. 1998 Nov 24;95(24):14500-5 PMID: 9826729
  55. HIV-1 coat protein neurotoxicity prevented by calcium channel antagonists.
    Science. 1990 Apr 20;248(4953):364-7 PMID: 2326646
  56. Cleavage of bid may amplify caspase-8-induced neuronal death following focally evoked limbic seizures.
    Neurobiol Dis. 2001 Aug;8(4):568-80 PMID: 11493022
  57. Cortical synaptic density is reduced in mild to moderate human immunodeficiency virus neurocognitive disorder. HNRC Group. HIV Neurobehavioral Research Center.
    Brain Pathol. 1999 Apr;9(2):209-17 PMID: 10219738
  58. Caspase activation: the induced-proximity model.
    Proc Natl Acad Sci U S A. 1999 Sep 28;96(20):10964-7 PMID: 10500109
  59. Tumor necrosis factor alpha-induced apoptosis in human neuronal cells: protection by the antioxidant N-acetylcysteine and the genes bcl-2 and crmA.
    Mol Cell Biol. 1995 May;15(5):2359-66 PMID: 7739519
  60. Increased expression of tumor necrosis factor-alpha receptors in the brains of patients with AIDS.
    J Acquir Immune Defic Syndr Hum Retrovirol. 1995 Dec 15;10(5):511-21 PMID: 8548330
  61. Effects of extracellular human immunodeficiency virus type 1 vpr protein in primary rat cortical cell cultures.
    J Neurovirol. 2000 Jun;6(3):202-20 PMID: 10878710
  62. Analysis of the critical domain in the V3 loop of human immunodeficiency virus type 1 gp120 involved in CCR5 utilization.
    J Virol. 1999 Oct;73(10):8216-26 PMID: 10482572
  63. Chemokine receptors in the human brain and their relationship to HIV infection.
    J Neurovirol. 1998 Jun;4(3):301-11 PMID: 9639073
  64. Effects of circulating tumor necrosis factor on the neuronal activity and expression of the genes encoding the tumor necrosis factor receptors (p55 and p75) in the rat brain: a view from the blood-brain barrier.
    Neuroscience. 1999;93(4):1449-64 PMID: 10501470
  65. 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 Jul 15;19(14):5932-41 PMID: 10407032
  66. Seminars in medicine of the Beth Israel Hospital, Boston. Dementia associated with the acquired immunodeficiency syndrome.
    N Engl J Med. 1995 Apr 6;332(14):934-40 PMID: 7877652
  67. Apoptotic neurons in brains from paediatric patients with HIV-1 encephalitis and progressive encephalopathy.
    Neuropathol Appl Neurobiol. 1995 Jun;21(3):208-17 PMID: 7477729
  68. Neuronal apoptosis in HIV infection in adults.
    Neuropathol Appl Neurobiol. 1995 Jun;21(3):218-27 PMID: 7477730
  69. Prevention of HIV-1 gp120-induced neuronal damage in the central nervous system of transgenic mice by the NMDA receptor antagonist memantine.
    Brain Res. 1996 Jan 15;706(2):303-7 PMID: 8822372
  70. Cleavage of BID by caspase 8 mediates the mitochondrial damage in the Fas pathway of apoptosis.
    Cell. 1998 Aug 21;94(4):491-501 PMID: 9727492
  71. Dendritic injury is a pathological substrate for human immunodeficiency virus-related cognitive disorders. HNRC Group. The HIV Neurobehavioral Research Center.
    Ann Neurol. 1997 Dec;42(6):963-72 PMID: 9403489
Article Info
Journal
The Journal of neuroscience : the official journal of the Society for Neuroscience
Abbr.
J Neurosci
ISSN
1529-2401
DOI
20026351
Email
gagarden@u.washington.edu
Published
2002-05-15
Pages
4015-24
Language
English
Region
United States
NLM ID
8102140
PMCID
PMC6757636
Subset
IM
Grants
Wellcome Trust · United Kingdom
External Links
PubMed source DOI: 20026351 PMC Full Text View journal details
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