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Activation of PARP by Oxidative Stress Induced by β-Amyloid: Implications for Alzheimer’s Disease

Abstract

Alzheimer’s disease (AD) is a major neurodegenerative disease of old age, characterised by progressive cognitive impairment, dementia and atrophy of the central nervous system. The pathological hallmarks include the accumulation of the peptide β-amyloid (Aβ) which itself is toxic to neurons in culture. Recently, it has been discovered that Aβ activates the protein poly(ADP-ribosyl) polymerase-1 (PARP-1) specifically in astrocytes, leading indirectly to neuronal cell death. PARP-1 is a DNA repair enzyme, normally activated by single strand breaks associated with oxidative stress, which catalyses the formation of poly ADP-ribose polymers from nicotinamide adenine dinucleotide (NAD+). The pathological over activation of PARP-1 causes depletion of NAD+ and leads to cell death. Here we review the relationship between AD and PARP-1, and explore the role played by astrocytes in neuronal death. AD has so far proven refractory to any effective treatment. Identification of these pathways represents a step towards a greater understanding of the pathophysiology of this devastating disease with the potential to explore novel therapeutic targets.

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References

  1. 1.

    Abeti R, Abramov AY, Duchen MR (2011) Beta-amyloid activates PARP causing astrocytic metabolic failure and neuronal death. Brain 34:1658–1672

  2. 2.

    Abramov AY, Canevari L, Duchen MR (2003) Changes in intracellular calcium and glutathione in astrocytes as the primary mechanism of amyloid neurotoxicity. J Neurosci 23:5088–5095

  3. 3.

    Abramov AY, Canevari L, Duchen MR (2004) Beta-amyloid peptides induce mitochondrial dysfunction and oxidative stress in astrocytes and death of neurons through activation of NADPH oxidase. J Neurosci 24:565–575

  4. 4.

    Abramov AY, Canevari L, Duchen MR (2004) Calcium signals induced by amyloid beta peptide and their consequences in neurons and astrocytes in culture. Biochim Biophys Acta 1742:81–87

  5. 5.

    Abramov AY, Jacobson J, Wientjes F, Hothersall J, Canevari L, Duchen MR (2005) Expression and modulation of an NADPH oxidase in mammalian astrocytes. J Neurosci 25(40):9176–9184

  6. 6.

    Abramov AY, Duchen MR (2005) The role of an astrocytic NADPH oxidase in the neurotoxicity of amyloid beta peptides. Philos Trans R Soc Lond B Biol Sci 360:2309–2314

  7. 7.

    Abramov AY, Duchen MR (2008) Mechanisms underlying the loss of mitochondrial membrane potential in glutamate excitotoxicity. Biochim Biophys Acta 1777:953–964

  8. 8.

    Abramov AY, Ionov M, Pavlov E, Duchen MR (2011) Membrane cholesterol content plays a key role in the neurotoxicity of β-amyloid: implications for Alzheimer’s disease. Aging Cell 10(4):595–603

  9. 9.

    Adamczyk A, Czapski GA, Jeśko H, Strosznajder RP (2005) Non A beta component of Alzheimer’s disease amyloid and amyloid beta peptides evoked poly(ADP-ribose) polymerase-dependent release of apoptosis-inducing factor from rat brain mitochondria. J Physiol Pharmacol 56(Suppl 2):5–13

  10. 10.

    Agostinho P, Cunha RA, Oliveira C (2010) Neuroinflammation, oxidative stress and the pathogenesis of Alzheimer’s Disease. Curr Pharm Des 16(25):2766–2778

  11. 11.

    Alano CC, Garnier P, Ying W, Higashi Y, Kauppinen TM, Swanson RA (2010) NAD+ depletion is necessary and sufficient for poly(ADP-ribose) polymerase-1-mediated neuronal death. J Neurosci 30(8):2967–2978

  12. 12.

    Alano CC, Tran A, Tao R, Ying W, Karliner JS, Swanson RA (2007) Differences among cell types in NAD(+) compartmentalization: a comparison of neurons, astrocytes, and cardiac myocytes. J Neurosci Res 85(15):3378–3385

  13. 13.

    Alberdi E, Sánchez-Gómez MV, Cavaliere F, Pérez-Samartín A, Zugaza JL, Trullas R, Domercq M, Matute C (2010) Amyloid beta oligomers induce Ca2+ dysregulation and neuronal death through activation of ionotropic glutamate receptors. Cell Calcium 47(3):264–272

  14. 14.

    Aliev G, Smith MA, de la Torre JC, Perry G (2004) Mitochondria as a primary target for vascular hypoperfusion and oxidative stress in Alzheimer’s disease. Mitochondrion 4(5–6):649–663

  15. 15.

    Ame JC, Spenlehauer C, de Murcia G (2004) The PARP superfamily. BioEssays 26:882–893

  16. 16.

    Andrabi SA, Dawson TM, Dawson VL (2008) Mitochondrial and nuclear cross talk in cell death: parthanatos. Ann N Y Acad Sci 1147:233–241

  17. 17.

    Blass JP, Gibson GE (1991) The role of oxidative abnormalities in the pathophysiology of Alzheimer’s disease. Rev Neurol (Paris) 147:513–525

  18. 18.

    Blennow K, de Leon MJ, Zetterberg H (2006) Alzheimer’s disease. Lancet 368:387–403

  19. 19.

    Bedard K, Krause KH (2007) The NOX family of ROS-generating NADPH oxidases: physiology and pathophysiology. Physiol Rev 87:245–313

  20. 20.

    Bomboi G, Castello L, Cosentino F, Giubilei F, Orzi F, Volpe M (2010) Alzheimer’s disease and endothelial dysfunction. Neurol Sci 31:1–8

  21. 21.

    Burkle A, Diefenbach J, Brabeck C, Beneke S (2005) Ageing and PARP. Pharmacol Res 52:93–99

  22. 22.

    Camandola S, Mattson MP (2011) Aberrant subcellular neuronal calcium regulation in aging and Alzheimer’s disease. Biochim Biophys Acta 1813(5):965–973 (Epub 2010 Oct 13)

  23. 23.

    Canevari L, Abramov AY, Duchen MR (2004) Toxicity of amyloid beta peptide: tales of calcium, mitochondria, and oxidative stress. Neurochem Res 29:637–650

  24. 24.

    Canevari L, Clark JB, Bates TE (1999) Beta-Amyloid fragment 25–35 selectively decreases complex IV activity in isolated mitochondria. FEBS Lett 457(1):131–134

  25. 25.

    Capone R, Jang H, Kotler SA, Kagan BL, Nussinov R, Lal R (2012) Probing structural features of Alzheimer’s amyloid-β pores in bilayers using site-specific amino acid substitutions. Biochemistry 51(3):776–785

  26. 26.

    Casas C, Sergeant N, Itier JM, Blanchard V, Wirths O, van der Kolk N, Vingtdeux V, van de Steeg E, Ret G, Canton T, Drobecq H, Clark A, Bonici B, Delacourte A, Benavides J, Schmitz C, Tremp G, Bayer TA, Benoit P, Pradier L (2004) Massive CA1/2 neuronal loss with intraneuronal and N-terminal truncated Abeta42 accumulation in a novel Alzheimer transgenic model. Am J Pathol 165(4):1289–1300

  27. 27.

    Casley CS, Canevari L, Land JM, Clark JB, Sharpe MA (2002) Beta-amyloid inhibits integrated mitochondrial respiration and key enzyme activities. J Neurochem 80(1):91–100

  28. 28.

    Chen Q, Vazquez EJ, Moghaddas S, Hoppel CL, Lesnefsky EJ (2003) Production of reactive oxygen species by mitochondria: central role of complex III. J Biol Chem 278:36027–36031

  29. 29.

    Chiarugi A (2002) Poly(ADP-ribose) polymerase: killer or conspirator? The ‘suicide hypothesis’ revisited. Trends Pharmacol Sci 23:122–129

  30. 30.

    Chung YH, Joo KM, Lee YJ, Shin DH, Cha CI (2004) Reactive astrocytes express PARP in the central nervous system of SOD(G93A) transgenic mice. Brain Res 1–2:199–204

  31. 31.

    Corder EH, Saunders AM, Strittmatter WJ, Schmechel DE, Gaskell PC, Small GW, Roses AD, Haines JL, Pericak-Vance MA (1993) Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer’s disease in late onset families. Science 261:921–923

  32. 32.

    Corona C, Pensalfini A, Frazzini V, Sensi SL (2011) New therapeutic targets in Alzheimer’s disease: brain deregulation of calcium and zinc. Cell Death Dis 2:e176

  33. 33.

    Dahlgren KN, Manelli AM, Stine WB Jr, Baker LK, Krafft GA, LaDu MJ (2002) Oligomeric and fibrillar species of amyloid-beta peptides differentially affect neuronal viability. J Biol Chem 277:32046–32053

  34. 34.

    D’Amours D, Desnoyers S, D’Silva I, Poirier GG (1999) Poly(ADP-ribosyl)ation reactions in the regulation of nuclear functions. Biochem J 342(Pt 2):249–268

  35. 35.

    Dantzer F, Nasheuer HP, Vonesch JL, de Murcia G, Ménissier-de Murcia J (1998) Functional association of poly(ADP-ribose) polymerase with DNA polymerase alpha-primase complex: a link between DNA strand break detection and DNA replication. Nucleic Acids Res 26(8):1891–1898

  36. 36.

    Dantzer F, Schreiber V, Niedergang C, Trucco C, Flatter E, De La Rubia G, Oliver J, Rolli V, Ménissier-de Murcia J, de Murcia G (1999) Involvement of poly(ADP-ribose) polymerase in base excision repair. Biochimie 81(1–2):69–75 (Review)

  37. 37.

    Davidovic L, Vodenicharov M, Affar EB, Poirier GG (2001) Importance of poly(ADP-ribose) glycohydrolase in the control of poly(ADP-ribose) metabolism. Exp Cell Res 268:7–13

  38. 38.

    David KK, Andrabi SA, Dawson TM, Dawson VL (2009) Parthanatos, a messenger of death. Front Biosci 1(14):1116–1128

  39. 39.

    de Murcia G, Ménissier de Murcia J (1994) Poly(ADP-ribose) polymerase: a molecular nick-sensor. Trends Biochem Sci 19(4):172–176

  40. 40.

    de Murcia G, Jacobson M, Shall S (1995) Regulation by ADP-ribosylation. Trends Cell Biol 5(2):78–81

  41. 41.

    Diefenbach J, Burkle A (2005) Introduction to poly(ADP-ribose) metabolism. Cell Mol Life Sci 62:721–730

  42. 42.

    Du H, Guo L, Yan S, Sosunov AA, McKhann GM, Yan SS (2010) Early deficits in synaptic mitochondria in an Alzheimer’s disease mouse model. Proc Natl Acad Sci USA 107:18670–18675

  43. 43.

    Duan Y, Gross RA, Sheu SS (2007) Ca2 + -dependent generation of mitochondrial reactive oxygen species serves as a signal for poly(ADP-ribose) polymerase-1 activation during glutamate excitotoxicity. J Physiol 585:741–758

  44. 44.

    Eliasson MJ, Sampei K, Mandir AS, Hurn PD, Traystman RJ, Bao J, Pieper A, Wang ZQ, Dawson TM, Snyder SH, Dawson VL (1997) Poly(ADP-ribose) polymerase gene disruption renders mice resistant to cerebral ischemia. Nat Med 3:1089–1095

  45. 45.

    Frisoni GB, Pievani M, Testa C, Sabattoli F, Bresciani L, Bonetti M, Beltramello A, Hayashi KM, Toga AW, Thompson PM (2007) The topography of grey matter involvement in early and late onset Alzheimer’s disease. Brain 130(Pt 3):720–730

  46. 46.

    Hardy J, Allsop D (1991) Amyloid deposition as the central event in the aetiology of Alzheimer’s disease. Trends Pharmacol Sci 12:383–388

  47. 47.

    Herceg Z, Wang ZQ (2001) Functions of poly(ADP-ribose) polymerase (PARP) in DNA repair, genomic integrity and cell death. Mutat Res 477:97–110

  48. 48.

    Hirai K, Aliev G, Nunomura A, Fujioka H, Russell RL, Atwood CS, Johnson AB, Kress Y, Vinters HV, Tabaton M, Shimohama S, Cash AD, Siedlak SL, Harris PL, Jones PK, Petersen RB, Perry G, Smith MA (2001) Mitochondrial abnormalities in Alzheimer’s disease. J Neurosci 21:3017–3023

  49. 49.

    Howlett DR, Bowler K, Soden PE, Riddell D, Davis JB, Richardson JC, Burbidge SA, Gonzalez MI, Irving EA, Lawman A, Miglio G, Dawson EL, Howlett ER, Hussain I (2008) Abeta deposition and related pathology in an APP x PS1 transgenic mouse model of Alzheimer’s disease. Histol Histopathol 23:67–76

  50. 50.

    Kagan BL, Azimov R, Azimova R (2004) Amyloid peptide channels. J Membr Biol 202(1):1–10

  51. 51.

    Keelan J, Allen NJ, Antcliffe D, Pal S, Duchen MR (2001) Quantitative imaging of glutathione in hippocampal neurons and glia in culture using monochlorobimane. J Neurosci Res 66(5):873–884

  52. 52.

    Kauppinen TM, Suh SW, Higashi Y, Berman AE, Escartin C, Won SJ, Wang C, Cho SH, Gan L, Swanson RA (2011) Poly(ADP-ribose)polymerase-1 modulates microglial responses to amyloid β. J Neuroinflammation 8:152

  53. 53.

    Lambert JC et al (2002) Contribution of APOE promoter polymorphisms to Alzheimer’s disease risk. Neurology 59:59–66

  54. 54.

    Lee CY, Landreth GE (2010) The role of microglia in amyloid clearance from the AD brain. J Neural Transm 117:949–960

  55. 55.

    Lee HP, Pancholi N, Esposito L, Previll LA, Wang X, Zhu X, Smith MA, Lee HG (2012) Early induction of oxidative stress in mouse model of Alzheimer disease with reduced mitochondrial superoxide dismutase activity. PLoS One 7(1):e28033

  56. 56.

    Lesnefsky EJ, Moghaddas S, Tandler B, Kerner J, Hoppel CL (2001) Mitochondrial dysfunction in cardiac disease: ischemia–reperfusion, aging, and heart failure. J Mol Cell Cardiol 33:1065–1089

  57. 57.

    Lewis J, McGowan E, Rockwood J, Melrose H, Nacharaju P, Van SM, Gwinn-Hardy K, Paul MM, Baker M, Yu X, Duff K, Hardy J, Corral A, Lin WL, Yen SH, Dickson DW, Davies P, Hutton M (2000) Neurofibrillary tangles, amyotrophy and progressive motor disturbance in mice expressing mutant (P301L) tau protein. Nat Genet 25:402–405

  58. 58.

    Liu HP, Lin WY, Wu BT, Liu SH, Wang WF, Tsai CH, Lee CC, Tsai FJ (2010) Evaluation of the poly(ADP-ribose) polymerase-1 gene variants in Alzheimer’s disease. J Clin Lab Anal 24:182–186

  59. 59.

    Love S, Barber R, Wilcock GK (1999) Increased poly(ADP-ribosyl)ation of nuclear proteins in Alzheimer’s disease. Brain 122(Pt 2):247–253

  60. 60.

    Mandir AS, Poitras MF, Berliner AR, Herring WJ, Guastella DB, Feldman A, Poirier GG, Wang ZQ, Dawson TM, Dawson VL (2000) NMDA but not non-NMDA excitotoxicity is mediated by Poly(ADP-ribose) polymerase. J Neurosci 20:8005–8011

  61. 61.

    Mandir AS, Przedborski S, Jackson-Lewis V, Wang ZQ, Simbulan-Rosenthal CM, Smulson ME, Hoffman BE, Guastella DB, Dawson VL, Dawson TM (1999) Poly(ADP-ribose) polymerase activation mediates 1-methyl-4-phenyl-1, 2,3,6-tetrahydropyridine (MPTP)-induced parkinsonism. Proc Natl Acad Sci USA 96:5774–5779

  62. 62.

    McGeer EG, McGeer PL (2005) Abeta immunotherapy and other means to remove amyloid. Curr Drug Targets CNS Neurol Disord 4(5):569–573 (Review)

  63. 63.

    Medeiros R, Baglietto-Vargas D, Laferla FM (2010) The role of tau in Alzheimer’s disease and related disorders. CNS Neurosci Ther 17(5):514–524

  64. 64.

    Mattson MP, Chan SL (2003) Neuronal and glial calcium signaling in Alzheimer’s disease. Cell Calcium 34:385–397

  65. 65.

    Moroni F (2008) Poly(ADP-ribose)polymerase 1 (PARP-1) and postischemic brain damage. Curr Opin Pharmacol 8:96–103

  66. 66.

    Moroni F, Cozzi A, Chiarugi A, Formentini L, Camaioni E, Pellegrini-Giampietro D, Chen Y, Liang S, Zaleska M, Gonzales C, Wood A, Pellicciari R (2012) Long-lasting neuroprotection and neurological improvement in stroke models with new, potent and brain permeable inhibitors of poly(ADP-ribose) polymerase. Br J Pharmacol 165:1487–1500

  67. 67.

    Muiras ML, Burkle A (2000) Defending genomic stability over life span: a proposed role for PARP-1. Exp Gerontol 35:703–709

  68. 68.

    Myllykangas L, Polvikoski T, Reunanen K, Wavrant-De VF, Ellis C, Hernandez D, Sulkava R, Kontula K, Verkkoniemi A, Notkola IL, Hardy J, Perez-Tur J, Haltia MJ, Tienari PJ (2002) ApoE epsilon3-haplotype modulates Alzheimer beta-amyloid deposition in the brain. Am J Med Genet 114:288–291

  69. 69.

    Noh KM, Koh JY (2000) Induction and activation by zinc of NADPH oxidase in cultured cortical neurons and astrocytes. J Neurosci 20:RC111

  70. 70.

    Oliver FJ, Menissier-de Murcia J, de Murcia G (1999) Poly(ADP-ribose) polymerase in the cellular response to DNA damage, apoptosis, and disease. Am J Hum Genet 64(5):1282–1288

  71. 71.

    Poirier J, Davignon J, Bouthillier D, Kogan S, Bertrand P, Gauthier S (1993) Apolipoprotein E polymorphism and Alzheimer’s disease. Lancet 342:697–699

  72. 72.

    Readnower RD, Sauerbeck AD, Sullivan PG (2011) Mitochondria, amyloid β, and Alzheimer’s Disease. Int J Alzheimers Dis 22(2011):104545

  73. 73.

    Rouleau M, Aubin RA, Poirier GG (2004) Poly(ADP-ribosyl)ated chromatin domains: access granted. J Cell Sci 117(Pt 6):815–825

  74. 74.

    Supnet C, Bezprozvanny I (2011) Presenilins function in ER calcium leak and Alzheimer’s disease pathogenesis. Cell Calcium 50(3):303–309

  75. 75.

    Sarnaik AA, Conley YP, Okonkwo DO, Barr TL, Fink EL, Szabo C, Kochanek PM, Clark RS (2010) Influence of PARP-1 polymorphisms in patients after traumatic brain injury. J Neurotrauma 27:465–471

  76. 76.

    Schreiber V, Dantzer F, Ame JC, de Murcia G (2006) Poly(ADP-ribose): novel functions for an old molecule. Nat Rev Mol Cell Biol 7:517–528

  77. 77.

    Sheehan JP, Swerdlow RH, Miller SW, Davis RE, Parks JK, Parker WD, Tuttle JB (1997) Calcium homeostasis and reactive oxygen species production in cells transformed by mitochondria from individuals with sporadic Alzheimer’s disease. J Neurosci 17(12):4612–4622

  78. 78.

    Snyder SW, Ladror US, Wade WS, Wang GT, Barrett LW, Matayoshi ED, Huffaker HJ, Krafft GA, Holzman TF (1994) Amyloid-beta aggregation: selective inhibition of aggregation in mixtures of amyloid with different chain lengths. Biophys J 67:1216–1228

  79. 79.

    Strosznajder JB, Czapski GA, Adamczyk A, Strosznajder RP (2012) Poly(ADP-ribose) Polymerase-1 in Amyloid Beta Toxicity and Alzheimer’s Disease. Mol Neurobiol 46(1):78–84

  80. 80.

    Suh SW, Aoyama K, Alano CC, Anderson CM, Hamby AM, Swanson RA (2007) Zinc inhibits astrocyte glutamate uptake by activation of poly(ADP-ribose) polymerase-1. Mol Med 13:344–349

  81. 81.

    Susin SA, Lorenzo HK, Zamzami N, Marzo I, Snow BE, Brothers GM, Mangion J, Jacotot E, Costantini P, Loeffler M, Larochette N, Goodlett DR, Aebersold R, Siderovski DP, Penninger JM, Kroemer G (1999) Molecular characterization of mitochondrial apoptosis-inducing factor. Nature 397:441–446

  82. 82.

    Ying W, Garnier P, Swanson RA (2003) NAD+ repletion prevents PARP-1-induced glycolytic blockade and cell death in cultured mouse astrocytes. Biochem Biophys Res Commun 308:809–813

  83. 83.

    Younkin SG (1998) The role of A beta 42 in Alzheimer’s disease. J Physiol Paris 92:289–292

  84. 84.

    Wallace DC (2000) Mitochondrial defects in cardiomyopathy and neuromuscular disease. Am Heart J 139:S70–S85

  85. 85.

    Wang Y, Dawson VL, Dawson TM (2009) Poly(ADP-ribose) signals to mitochondrial AIF: a key event in parthanatos. Exp Neurol 218:193–202

  86. 86.

    Wang Y, Kim NS, Li X, Greer PA, Koehler RC, Dawson VL, Dawson TM (2009) Calpain activation is not required for AIF translocation in PARP-1-dependent cell death (parthanatos). J Neurochem 110(2):687–696 (Epub 2009 May 13)

  87. 87.

    Wang Y, Kim NS, Haince JF, Kang HC, David KK, Andrabi SA, Poirier GG, Dawson VL, Dawson TM (2011) Poly(ADP-ribose) (PAR) binding to apoptosis-inducing factor is critical for PAR polymerase-1-dependent cell death (parthanatos). Sci Signal ra4(167):20

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Correspondence to Rosella Abeti.

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Special Issue: In Honor of Leif Hertz.

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Abeti, R., Duchen, M.R. Activation of PARP by Oxidative Stress Induced by β-Amyloid: Implications for Alzheimer’s Disease. Neurochem Res 37, 2589–2596 (2012). https://doi.org/10.1007/s11064-012-0895-x

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Keywords

  • Alzheimer’s disease
  • β-amyloid
  • PARP-1
  • Astrocytes
  • Oxidative stress and mitochondria