Abstract
HIV-1-associated neurocognitive disorder (HAND) is a neurodegenerative disease resulting in various clinical manifestations, characterized by neuroinflammation, oxidative stress, and related events. Neuronal damage in HAND is felt to be mainly indirect: microglial cells infected by HIV-1 increase the production of cytokines and release HIV-1 proteins, the most likely neurotoxins, among which are the envelope proteins gp120 and gp41 and the nonstructural proteins Nef, Rev, Vpr, and Tat. We review and discuss here different methods used in the assessment of apoptosis and neuronal loss in different experimental, acute and chronic, models of HAND. We also briefly consider how these techniques help to evaluate the effects of gene delivery of antioxidant enzymes in animal models of HAND.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
Similar content being viewed by others
References
McArthur JC, Hoover DR, Bacellar H et al (1993) Dementia in AIDS patients: incidence and risk factors. Multicenter AIDS Cohort Study. Neurology 43:2245–2252
Major EO, Rausch D, Marra C et al (2000) HIV-associated dementia. Science 288:440–442
Koutsilieri E, Sopper S, Scheller C et al (2002) Parkinsonism in HIV dementia. J Neural Transm 109:767–775
Antinori A, Arendt G, Becker JT et al (2007) Updated research nosology for HIV-associated neurocognitive disorders. Neurology 69:1789–1799
Woods SP, Moore DJ, Weber E et al (2009) Cognitive neuropsychology of HIV-associated neurocognitive disorders. Neuropsychol Rev 19:152–168
McArthur JC, Brew BJ, Nath A (2005) Neurological complications of HIV infection. Lancet Neurol 4:543–555
Nath A, Sacktor N (2006) Influence of highly active antiretroviral therapy on persistence of HIV in the central nervous system. Curr Opin Neurol 19:358–361
Ances BM, Ellis RJ (2007) Dementia and neurocognitive disorders due to HIV-1 infection. Semin Neurol 27:86–92
Mattson MP, Haughey NJ, Nath A (2005) Cell death in HIV dementia. Cell Death Differ 12:893–904
Rumbaugh JA, Nath A (2006) Developments in HIV neuropathogenesis. Curr Pharm Des 12:1023–1044
Gonzalez-Scarano F, Martin-Garcia J (2005) The neuropathogenesis of AIDS. Nat Rev Immunol 5:69–81
Kaul M, Garden GA, Lipton SA (2001) Pathways to neuronal injury and apoptosis in HIV-associated dementia. Nature 410:988–994
van de Bovenkamp M, Nottet HS, Pereira CF (2002) Interactions of human immunodeficiency virus-1 proteins with neurons: possible role in the development of human immunodeficiency virus-1 associated dementia. Eur J Clin Invest 32:619–627
Garden GA, Guo W, Jayadev S et al (2004) HIV associated neurodegeneration requires p53 in neurons and microglia. FASEB J 18:1141–1143
Xu Y, Kulkosky J, Acheampong E et al (2004) HIV-1-mediated apoptosis of neuronal cells: proximal molecular mechanisms of HIV-1-induced encephalopathy. Proc Natl Acad Sci U S A 101:7070–7075
Meucci O, Fatatis A, Simen AA et al (1998) Chemokines regulate hippocampal neuronal signalling and gp120 neurotoxicity. Proc Natl Acad Sci U S A 95:14500–14505
Kaul M, Lipton SA (1999) Chemokines and activated macrophages in HIV gp120-induced neuronal apoptosis. Proc Natl Acad Sci U S A 96:8212–8216
Eugenin EA, D’Aversa TG, Lopez L et al (2003) MCP-1 (CCL2) protects human neurons and astrocytes from NMDA or HIV-tat-induced apoptosis. J Neurochem 85:1299–1311
Ghezzi S, Noolan DM, Aluigi MG et al (2000) Inhibition of CXCR-3-dependent HIV-1 infection by extracellular HIV-1 Tat. Biochem Biophys Res Commun 270:992–996
Magnuson DS, Knudsen BE, Geiger JD et al (1995) Human immunodeficiency virus type 1 tat activates non-N-methyl-o-aspartate excitatory amino receptors and causes neurotoxicity. Ann Neurol 37:373–380
Bonavia R, Bajetto A, Barbero S et al (2001) HIV-1 Tat causes apoptosis death and calcium homeostasis alterations in rat neurons. Biochem Biophys Res Commun 288:301–308
Haughey NJ, Cutler RG, Tamara A et al (2004) Perturbation of sphingolipid metabolism and ceramide production in HIV-dementia. Ann Neurol 5:257–267
Kruman LL, Nath A, Mattson MP (1998) HIV-1 protein Tat induces apoptosis of hippocampal neurons by a mechanism involving caspase activation, calcium overload, and oxidative stress. Exp Neurol 154:276–288
Nath A, Haughey NJ, Jones M et al (2000) Synergistic neurotoxicity by human immunodeficiency virus proteins tat and gp120: protection by memantine. Ann Neurol 47:186–194
Hurtrel M, Ganiere JP, Guelfi JF et al (1992) Comparison of early and late feline immunodeficiency virus encephalopathies. AIDS 6:399–406
Thormar H (2005) Maedi-Visna virus and its relationship to human deficiency virus. AIDS Rev 7:233–245
Lackner AA, Veazey RS (2007) Current concepts in AIDS pathogenesis: insights from the SIV/macaque model. Annu Rev Med 58:461–476
Toggas SM, Masliah E, Rockenstein EM et al (1994) Central nervous system damage produced by expression of the HIV-1 coat protein gp120 in transgenic mice. Nature 367:188–193
Bruce-Keller AJ, Turchan-Cholewo J, Smart EJ et al (2008) Morphine causes rapid increases in glial activation and neuronal injury in the striatum of inducible HIV-1 Tat transgenic mice. Glia 56:1414–1427
Agrawal L, Louboutin JP, Reyes BAS et al (2006) Antioxidant enzyme gene delivery to protect from HIV-1 gp120-induced neuronal apoptosis. Gene Ther 13:1645–1656
Louboutin JP, Reyes BAS, Agrawal L et al (2007) Strategies for CNS-directed gene delivery: in vivo gene transfer to the brain using SV40-derived vectors. Gene Ther 14:939–949
Louboutin JP, Agrawal L, Reyes BAS et al (2007) Protecting neurons from HIV-1 gp120-induced oxidant stress using both localized intracerebral and generalized intraventricular administration of antioxidant enzymes delivered by SV40-derived vectors. Gene Ther 14:1650–1661
Louboutin JP, Agrawal L, Reyes BAS et al (2012) Gene delivery of antioxidant enzymes inhibits HIV-1 gp120-induced expression of caspases. Neuroscience 214:68–77
Nosheny RL, Bachis A, Acquas E et al (2004) Human immunodeficiency virus type 1 glycoprotein gp120 reduces the levels of brain-derived neurotrophic factor in vivo: potential implication for neuronal cell death. Eur J Neurosci 20:2857–2864
Louboutin JP, Agrawal L, Reyes BAS et al (2009) HIV-1 gp120 neurotoxicity proximally and at a distance from the point of exposure: protection by rSV40 delivery of antioxidant enzymes. Neurobiol Dis 34:462–476
Louboutin JP, Agrawal L, Reyes BAS et al (2010) HIV-1 gp120-induced injury to the blood-brain barrier: role of metalloproteinases 2 and 9 and relationship to oxidative stress. J Neuropathol Exp Neurol 69:801–816
Louboutin JP, Reyes BAS, Agrawal L et al (2010) Blood-brain barrier abnormalities caused by exposure to HIV-1 gp120 - protection by gene delivery of antioxidant enzymes. Neurobiol Dis 38:313–325
Louboutin JP, Reyes BAS, Agrawal L et al (2010) HIV-1 gp120-induced neuroinflammation: relationship to neuron loss and protection by rSV40-delivered antioxidant enzymes. Exp Neurol 221:231–245
Agrawal L, Louboutin JP, Marusich E et al (2010) Dopaminergic neurotoxicity of HIV-1 gp120: reactive oxygen species as signaling intermediates. Brain Res 1306:116–130
Louboutin JP, Reyes BAS, Agrawal L et al (2011) HIV-1 gp120 upregulates matrix metalloproteinases and their inhibitors in a rat model of HIV encephalopathy. Eur J Neurosci 34:2015–2020
Louboutin JP, Agrawal L, Reyes BAS et al (2009) A rat model of human immunodeficiency virus-1 encephalopathy using envelope glycoprotein gp120 expression delivered by SV40 vectors. J Neuropathol Exp Neurol 68:456–473
Louboutin JP, Agrawal L, Reyes BAS et al (2014) Oxidative stress is associated with neuroinflammation in animal models of HIV-1 Tat neurotoxicity. Antioxidants 3:414–438
Agrawal L, Louboutin JP, Reyes BAS et al (2012) HIV-1 Tat neurotoxicity: a model of acute and chronic exposure, and neuroprotection by gene delivery of antioxidant enzymes. Neurobiol Dis 45:657–670
Ikonomidou C, Bosch F, Miksa M et al (1999) Blockade of NMDA receptors and apoptotic neurodegeneration in the developing brain. Science 283:70–74
Ribe EM, Serrano-Saiz E, Akpan N et al (2008) Mechanisms of neuronal death in disease: defining the models and the players. Biochem J 415:165–182
Madden SD, Cotter TG (2008) Cell death in brain development and degeneration: control of caspase expression may be key! Mol Neurobiol 37:1–6
Sims NR, Muyderman H (2010) Mitochondria, oxidative metabolism and cell death in stroke. Biochim Biophys Acta 1802:80–91
Broughton BRS, Reutens DC, Sobey CG (2009) Apoptotic mechanisms after cerebral ischemia. Stroke 40:e331–e339
Rohn TT (2010) The role of caspases in Alzheimer’s disease: potential novel therapeutic opportunities. Apoptosis 15:1403–1409
Petito CK, Roberts B (1995) Evidence of apoptotic cell death in HIV encephalitis. Am J Pathol 146:1121–1130
Fujikawa DG (2015) The role of excitotoxic programmed necrosis in acute brain injury. Comput Struct Biotechnol J 13:212–221
Bottone MG, Fanizzi FP, Bernocchi G (2015) In vivo and in vitro immunohistochemical visualization of neural cell apoptosis and autophagy. In: Merighi A, Lossi L (eds) Immunocytochemistry and related techniques, vol 101, Neuromethods. Springer Protocols. Springer Science + Business Media, Humana Press, New York, NY, pp 153–178
Agrawal L, Louboutin JP, Strayer DS (2007) Preventing HIV-1 Tat-induced neuronal apoptosis using antioxidant enzymes: mechanistic and therapeutic implications. Virology 363:462–472
Louboutin JP, Marusich E, Fisher-Perkins J et al (2011) Gene transfer to the Rhesus monkey brain using SV40-derived vectors is durable and safe. Gene Ther 18:682–691
Louboutin JP, Chekmasova AA, Marusich E et al (2010) Efficient CNS gene delivery by intravenous injection. Nat Methods 7:905–907
Louboutin JP, Reyes BAS, Agrawal L et al (2012) Intracisternal rSV40 administration provides effective pan-CNS transgene expression. Gene Ther 19:114–118
Paxinos G, Watson C (1986) The rat brain in stereotaxic coordinates, 2nd edn. Academic, New York, NY
Louboutin JP (2015) Immunocytochemical assessment of blood-brain barrier structure, function, and damage. In: Merighi A, Lossi L (eds) Immunocytochemistry and related techniques, vol 101, Neuromethods. Springer Protocols. Springer Science + Business Media, Humana Press, New York, NY, pp 225–253
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2016 Springer Science+Business Media New York
About this protocol
Cite this protocol
Louboutin, JP., Reyes, B., Agrawal, L., Van Bockstaele, E., Strayer, D.S. (2016). Assessment of Apoptosis and Neuronal Loss in Animal Models of HIV-1-Associated Neurocognitive Disorders. In: Van Bockstaele, E. (eds) Transmission Electron Microscopy Methods for Understanding the Brain. Neuromethods, vol 115. Humana Press, New York, NY. https://doi.org/10.1007/7657_2015_96
Download citation
DOI: https://doi.org/10.1007/7657_2015_96
Published:
Publisher Name: Humana Press, New York, NY
Print ISBN: 978-1-4939-3638-0
Online ISBN: 978-1-4939-3640-3
eBook Packages: Springer Protocols