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

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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.

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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).

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Correspondence to Ming Xiao.

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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).

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