Advertisement

Springer Nature is making Coronavirus research free. View research | View latest news | Sign up for updates

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

  • 485 Accesses

  • 8 Citations

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.

This is a preview of subscription content, log in to check access.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8

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):e31870

  2. Andersen JK (2004) Oxidative stress in neurodegeneration: cause or consequence? Nat Med 10:S18–S25

  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):707–717

  4. Barja G (2004) Free radicals and aging. Trends Neurosci 27(10):595–600

  5. Bishop NA, Lu T, Yankner BA (2010) Neural mechanisms of ageing and cognitive decline. Nature 464(7288):529–535

  6. Burke SN, Barnes CA (2010) Senescent synapses and hippocampal circuit dynamics. Trends Neurosci 33(3):153–161

  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):e32015

  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):529–542

  9. Chen JH, Hales CN, Ozanne SE (2007) DNA damage, cellular senescence and organismal ageing: causal or correlative? Nucleic Acids Res 35(22):7417–7428

  10. Colangelo AM, Cirillo G, Lavitrano ML, Alberghina L, Papa M (2012) Targeting reactive astrogliosis by novel biotechnological strategies. Biotechnol Adv 30(1):261–271

  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):439–442

  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):303–311

  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):1216–1225

  14. Franklin KBJ, Paxinos G (2008) The mouse brain in stereotaxic coordinates, 2nd edn. Elsevier, Amsterdam

  15. Herrera-Mundo N, Sitges M (2010) Mechanisms underlying striatal vulnerability to 3-nitropropionic acid. J Neurochem 114(2):597–605

  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):1897–1905

  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):164–168

  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):252–257

  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):1054–1068

  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):1082–1087

  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):337–341

  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):16545–16553

  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):387–392

  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):538–547

  25. Lowry OH, Rosebrogh NJ, FARR AL, Radell RJ (1951) Protein measurement with the Folin phenol reagent. J Biol Chem 193(1):265–275

  26. Lushchak VI (2012) Glutathione homeostasis and functions: potential targets for medical interventions. J Amino Acids 2012:736837

  27. Mrak RE, Griffin ST, Graham DI (1997) Aging-associated changes in human brain. J Neuropathol Exp Neurol 56(12):1269–1275

  28. Middeldorp J, Hol EM (2011) GFAP in health and disease. Prog Neurobiol 93(3):421–443

  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):29–36

  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):1432–1437

  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):e36209

  32. Park IK, Morrison SJ, Clarke MF (2004) Bmi1, stem cells, and senescence regulation. J Clin Invest 113(2):175–179

  33. Ransom BR, Ransom CB (2012) Astrocytes: multitalented stars of the central nervous system. Methods Mol Biol 814:3–7

  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):1498–1505

  35. Serrano F, Klann E (2004) Reactive oxygen species and synaptic plasticity in the aging hippocampus. Ageing Res Rev 3(4):431–443

  36. Sohal RS, Orr WC (2012) The redox stress hypothesis of aging. Free Radic Biol Med 52(3):539–555

  37. Terman A, Brunk UT (2006) Oxidative stress, accumulation of biological ‘garbage’, and aging. Antioxid Redox Signal 8(1–2):197–204

  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):757–769

  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 8:138

  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):e10748

  41. Wilson JX (1997) Antioxidant defense of the brain: a role for astrocytes. Can J Physiol Pharmacol 75(10–11):1149–1163

  42. Wood ZA, Schröder E, Harris JR, Poole LB (2003) Structure, mechanism and regulation of peroxiredoxins. Trends Biochem Sci 28(1):32–40

  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):5774–5783

  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):640–652

  45. Zinkel S, Gross A, Yang E (2006) BCL2 family in DNA damage and cell cycle control. Cell Death Differ 13(8):1351–1359

Download references

Acknowledgments

We would like to thank Professor Anton Berns in the Netherlands Cancer Institute for providing Bmi1+/− mice. This work was supported by grants from the National Natural Science Foundation of China (nos. 30971020 and 81271210 to M. Xiao, nos. 30830103 and 81230009 to D. Miao, and no. 30901578 to T. Wu).

Author information

Correspondence to Ming Xiao.

Electronic supplementary material

Below is the link to the electronic supplementary material.

ESM 1

PDF 170 kb

About this article

Cite this article

Gu, M., Shen, L., Bai, L. et al. Heterozygous knockout of the Bmi-1 gene causes an early onset of phenotypes associated with brain aging. AGE 36, 129–139 (2014). https://doi.org/10.1007/s11357-013-9552-9

Download citation

Keywords

  • Bmi-1
  • Brain aging
  • Reactive oxygen species
  • Reactive gliosis