AGE

, Volume 36, Issue 1, pp 129–139

Heterozygous knockout of the Bmi-1 gene causes an early onset of phenotypes associated with brain aging

  • Minxia Gu
  • Lihua Shen
  • Lei Bai
  • Junying Gao
  • Charles Marshall
  • Ting Wu
  • Jiong Ding
  • Dengshun Miao
  • Ming Xiao
Article

Abstract

Previous studies reported that the polycomb group gene Bmi-1 is downregulated in the aging brain. The aim of this study was to investigate whether decreased Bmi-1 expression accelerates brain aging by analyzing the brain phenotype of adult Bmi-1 heterozygous knockout (Bmi-1+/−) mice. An 8-month-old Bmi-1+/− brains demonstrated mild oxidative stress, revealed by significant increases in hydroxy radical and nitrotyrosine, and nonsignificant increases in reactive oxygen species and malonaldehyde compared with the wild-type littermates. Bmi-1+/− hippocampus had high apoptotic percentage and lipofuscin deposition in pyramidal neurons associated with upregulation of cyclin-dependent kinase inhibitors p19, p27, and p53 and downregulation of anti-apoptotic protein Bcl-2. Mild activation of astrocytes was also observed in Bmi-1+/− hippocampus. Furthermore, Bmi-1+/− mice showed mild spatial memory impairment in the Morris Water Maze test. These results demonstrate that heterozygous Bmi-1 gene knockout causes an early onset of age-related brain changes, suggesting that Bmi-1 has a role in regulating brain aging.

Keywords

Bmi-1 Brain aging Reactive oxygen species Reactive gliosis 

Supplementary material

11357_2013_9552_MOESM1_ESM.pdf (170 kb)
ESM 1PDF 170 kb

References

  1. Abdouh M, Chatoo W, El Hajjar J, David J, Ferreira J, Bernier G (2012) Bmi1 is down-regulated in the aging brain and displays antioxidant and protective activities in neurons. PLoS One 7(2):e31870PubMedCentralPubMedCrossRefGoogle Scholar
  2. Andersen JK (2004) Oxidative stress in neurodegeneration: cause or consequence? Nat Med 10:S18–S25PubMedCrossRefGoogle Scholar
  3. Assunção M, Santos-Marques MJ, Carvalho F, Lukoyanov NV, Andrade JP (2011) Chronic green tea consumption prevents age-related changes in rat hippocampal formation. Neurobiol Aging 32(4):707–717PubMedCrossRefGoogle Scholar
  4. Barja G (2004) Free radicals and aging. Trends Neurosci 27(10):595–600PubMedCrossRefGoogle Scholar
  5. Bishop NA, Lu T, Yankner BA (2010) Neural mechanisms of ageing and cognitive decline. Nature 464(7288):529–535PubMedCentralPubMedCrossRefGoogle Scholar
  6. Burke SN, Barnes CA (2010) Senescent synapses and hippocampal circuit dynamics. Trends Neurosci 33(3):153–161PubMedCentralPubMedCrossRefGoogle Scholar
  7. Cao G, Gu M, Zhu M, Gao J, Yin Y, Marshall C, Xiao M, Ding J, Miao D (2012) Bmi-1 absence causes premature brain degeneration. PLoS One 7(2):e32015PubMedCentralPubMedCrossRefGoogle Scholar
  8. Chatoo W, Abdouh M, David J, Champagne MP, Ferreira J, Rodier F, Bernier G (2009) The polycomb group gene Bmi1 regulates antioxidant defenses in neurons by repressing p53 pro-oxidant activity. J Neurosci 29(2):529–542PubMedCentralPubMedCrossRefGoogle Scholar
  9. Chen JH, Hales CN, Ozanne SE (2007) DNA damage, cellular senescence and organismal ageing: causal or correlative? Nucleic Acids Res 35(22):7417–7428PubMedCentralPubMedCrossRefGoogle Scholar
  10. Colangelo AM, Cirillo G, Lavitrano ML, Alberghina L, Papa M (2012) Targeting reactive astrogliosis by novel biotechnological strategies. Biotechnol Adv 30(1):261–271PubMedCrossRefGoogle Scholar
  11. Darwish RS, Amiridze N, Aarabi B (2007) Nitrotyrosine as an oxidative stress marker: evidence for involvement in neurologic outcome in human traumatic brain injury. J Trauma 63(2):439–442PubMedCrossRefGoogle Scholar
  12. de Freitas V, da Silva Porto P, Assunção M, Cadete-Leite A, Andrade JP, Paula-Barbosa MM (2004) Flavonoids from grape seeds prevent increased alcohol-induced neuronal lipofuscin formation. Alcohol Alcohol 39(4):303–311PubMedCrossRefGoogle Scholar
  13. Dong Q, Oh JE, Chen W, Kim R, Kim RH, Shin KH, McBride WH, Park NH, Kang MK (2011) Radioprotective effects of Bmi-1 involve epigenetic silencing of oxidase genes and enhanced DNA repair in normal human keratinocytes. J Invest Dermatol 131(6):1216–1225PubMedCrossRefGoogle Scholar
  14. Franklin KBJ, Paxinos G (2008) The mouse brain in stereotaxic coordinates, 2nd edn. Elsevier, AmsterdamGoogle Scholar
  15. Herrera-Mundo N, Sitges M (2010) Mechanisms underlying striatal vulnerability to 3-nitropropionic acid. J Neurochem 114(2):597–605PubMedCrossRefGoogle Scholar
  16. Hua X, Lei M, Zhang Y, Ding J, Han Q, Hu G, Xiao M (2007) Long-term d-galactose injection combined with ovariectomy serves as a new rodent model for Alzheimer’s disease. Life Sci 80(20):1897–1905PubMedCrossRefGoogle Scholar
  17. Jacobs JJ, Kieboom K, Marino S, DePinho RA, van Lohuizen M (1999) The oncogene and polycomb-group gene bmi-1 regulates cell proliferation and senescence through the ink4a locus. Nature 397(6715):164–168PubMedCrossRefGoogle Scholar
  18. Jin MH, Lee YH, Kim JM, Sun HN, Moon EY, Shong MH, Kim SU, Lee SH, Lee TH, Yu DY, Lee DS (2005) Characterization of neural cell types expressing peroxiredoxins in mouse brain. Neurosci Lett 381(3):252–257PubMedCrossRefGoogle Scholar
  19. Kim SU, Jin MH, Kim YS, Lee SH, Cho YS, Cho KJ, Lee KS, Kim YI, Kim GW, Kim JM, Lee TH, Lee YH, Shong M, Kim HC, Chang KT, Yu DY, Lee DS (2011) Peroxiredoxin II preserves cognitive function against age-linked hippocampal oxidative damage. Neurobiol Aging 32(6):1054–1068PubMedCrossRefGoogle Scholar
  20. Lei M, Hua X, Xiao M, Ding J, Han Q, Hu G (2008) Impairments of astrocytes are involved in the d-galactose-induced brain aging. Biochem Biophys Res Commun 369(4):1082–1087PubMedCrossRefGoogle Scholar
  21. Leung C, Lingbeek M, Shakhova O, Liu J, Tanger E, Saremaslani P, Van Lohuizen M, Marino S (2004) Bmi1 is essential for cerebellar development and is overexpressed in human medulloblastomas. Nature 428(6980):337–341PubMedCrossRefGoogle Scholar
  22. Li SK, Smith DK, Leung WY, Cheung AM, Lam EW, Dimri GP, Yao KM (2008) FoxM1c counteracts oxidative stress-induced senescence and stimulates Bmi-1 expression. J Biol Chem 283(24):16545–16553PubMedCrossRefGoogle Scholar
  23. Liu J, Cao L, Chen J, Song S, Lee IH, Quijano C, Liu H, Keyvanfar K, Chen H, Cao LY, Ahn BH, Kumar NG, Rovira II, Xu XL, van Lohuizen M, Motoyama N, Deng CX, Finkel T (2009) Bmi1 regulates mitochondrial function and the DNA damage response pathway. Nature 459(7245):387–392PubMedCrossRefGoogle Scholar
  24. Lugo-Huitrón R, Blanco-Ayala T, Ugalde-Muñiz P, Carrillo-Mora P, Pedraza-Chaverrí J, Silva-Adaya D, Maldonado PD, Torres I, Pinzón E, Ortiz-Islas E, López T, García E, Pineda B, Torres-Ramos M, Santamaría A, La Cruz VP (2011) On the antioxidant properties of kynurenic acid: free radical scavenging activity and inhibition of oxidative stress. Neurotoxicol Teratol 33(5):538–547PubMedCrossRefGoogle Scholar
  25. Lowry OH, Rosebrogh NJ, FARR AL, Radell RJ (1951) Protein measurement with the Folin phenol reagent. J Biol Chem 193(1):265–275PubMedGoogle Scholar
  26. Lushchak VI (2012) Glutathione homeostasis and functions: potential targets for medical interventions. J Amino Acids 2012:736837PubMedCentralPubMedCrossRefGoogle Scholar
  27. Mrak RE, Griffin ST, Graham DI (1997) Aging-associated changes in human brain. J Neuropathol Exp Neurol 56(12):1269–1275PubMedCrossRefGoogle Scholar
  28. Middeldorp J, Hol EM (2011) GFAP in health and disease. Prog Neurobiol 93(3):421–443PubMedCrossRefGoogle Scholar
  29. Mironov AA Jr, Mironov AA (1998) Estimation of subcellular organelle volume from ultrathin sections through centrioles with adiscretized version of the vertical rotator. J Microsc 192(Pt 1):29–36PubMedCrossRefGoogle Scholar
  30. Molofsky AV, He S, Bydon M, Morrison SJ, Pardal R (2005) Bmi-1 promotes neural stem cell self-renewal and neural development but not mouse growth and survival by repressing the p16Ink4a and p19Arf senescence pathways. Genes Dev 19(12):1432–1437PubMedCrossRefGoogle Scholar
  31. Nakamura S, Oshima M, Yuan J, Saraya A, Miyagi S, Konuma T, Yamazaki S, Osawa M, Nakauchi H, Koseki H, Iwama A (2012) Bmi1 confers resistance to oxidative stress on hematopoietic stem cells. PLoS One 7(5):e36209PubMedCentralPubMedCrossRefGoogle Scholar
  32. Park IK, Morrison SJ, Clarke MF (2004) Bmi1, stem cells, and senescence regulation. J Clin Invest 113(2):175–179PubMedCentralPubMedGoogle Scholar
  33. Ransom BR, Ransom CB (2012) Astrocytes: multitalented stars of the central nervous system. Methods Mol Biol 814:3–7PubMedCrossRefGoogle Scholar
  34. Rizo A, Olthof S, Han L, Vellenga E, de Haan G, Schuringa JJ (2009) Repression of BMI1 in normal and leukemic human CD34(+) cells impairs self-renewal and induces apoptosis. Blood 114(8):1498–1505PubMedCrossRefGoogle Scholar
  35. Serrano F, Klann E (2004) Reactive oxygen species and synaptic plasticity in the aging hippocampus. Ageing Res Rev 3(4):431–443PubMedCrossRefGoogle Scholar
  36. Sohal RS, Orr WC (2012) The redox stress hypothesis of aging. Free Radic Biol Med 52(3):539–555PubMedCentralPubMedCrossRefGoogle Scholar
  37. Terman A, Brunk UT (2006) Oxidative stress, accumulation of biological ‘garbage’, and aging. Antioxid Redox Signal 8(1–2):197–204PubMedCrossRefGoogle Scholar
  38. van der Lugt NM, Domen J, Linders K, van Roon M, Robanus-Maandag E, te Riele H, van der Valk M, Deschamps J, Sofroniew M, van Lohuizen M, Berns A (1994) Posterior transformation, neurological abnormalities, and severe hematopoietic defects in mice with a targeted deletion of the bmi-1 proto-oncogene. Genes Dev 8(7):757–769PubMedCrossRefGoogle Scholar
  39. VanGuilder HD, Bixler GV, Brucklacher RM, Farley JA, Yan H, Warrington JP, Sonntag WE, Freeman WM (2011) Concurrent hippocampal induction of MHC II pathway components and glial activation with advanced aging is not correlated with cognitive impairment. J Neuroinflammation 8:138PubMedCentralPubMedCrossRefGoogle Scholar
  40. Venkataraman S, Alimova I, Fan R, Harris P, Foreman N, Vibhakar R (2010) MicroRNA 128a increases intracellular ROS level by targeting Bmi-1 and inhibits medulloblastomacancer cell growth by promoting senescence. PLoS One 5(6):e10748PubMedCentralPubMedCrossRefGoogle Scholar
  41. Wilson JX (1997) Antioxidant defense of the brain: a role for astrocytes. Can J Physiol Pharmacol 75(10–11):1149–1163PubMedCrossRefGoogle Scholar
  42. Wood ZA, Schröder E, Harris JR, Poole LB (2003) Structure, mechanism and regulation of peroxiredoxins. Trends Biochem Sci 28(1):32–40PubMedCrossRefGoogle Scholar
  43. Zencak D, Lingbeek M, Kostic C, Tekaya M, Tanger E, Hornfeld D, Jaquet M, Munier FL, Schorderet DF, van Lohuizen M, Arsenijevic Y (2005) Bmi1 loss produces an increase in astroglial cells and a decrease in neural stem cell population and proliferation. J Neurosci 25(24):5774–5783PubMedCrossRefGoogle Scholar
  44. Zhang HW, Ding J, Jin JL, Guo J, Liu JN, Karaplis A, Goltzman D, Miao D (2010) Defects in mesenchymal stem cell self-renewal and cell fate determination lead to an osteopenic phenotype in Bmi-1 null mice. J Bone Miner Res 25(3):640–652PubMedCrossRefGoogle Scholar
  45. Zinkel S, Gross A, Yang E (2006) BCL2 family in DNA damage and cell cycle control. Cell Death Differ 13(8):1351–1359PubMedCrossRefGoogle Scholar

Copyright information

© American Aging Association 2013

Authors and Affiliations

  • Minxia Gu
    • 1
  • Lihua Shen
    • 1
  • Lei Bai
    • 1
  • Junying Gao
    • 1
  • Charles Marshall
    • 3
  • Ting Wu
    • 2
  • Jiong Ding
    • 1
  • Dengshun Miao
    • 1
  • Ming Xiao
    • 1
  1. 1.Department of Human AnatomyNanjing Medical UniversityNanjingChina
  2. 2.Department of Neurologythe First Affiliated Hospital of Nanjing Medical University NanjingJiangsuChina
  3. 3.Department of Rehabilitation SciencesUniversity of Kentucky Center for Excellence in Rural HealthHazardUSA

Personalised recommendations