Effects Of Heterozygous Deletion Of Bmi-1 Gene On The Mouse Brain Ageing

Bmi-1 gene is belonging to the polycomb gene family in a regulatory gene involved in cell proliferation and differentiation, oxidative homeostasis and mitochondrial DNA damage pathway, which is critical to the survival and development of the individual. Previous studies mianly focused on the roles of Bmi-1 on stem cell proliferation and differentiation, but its roles in the brain of aged mice, especially in the adult neurogenesis, mitochondrial function and maintaining oxidative and antioxidative balance are not very clear. In order to explore the roles of Bmi-1 in the brain ageing,in the present study, by use of 17-month old Bmi-1 heterozygous(+/-) mice, we observed changes in learning and memory-related behaviors and morphology. The results showed that there were no changes in general morphology such as skin, bones, weight, etc in Bmi-1+/- mice, but deficits in the long-term spatial memory function and the ability of memory damage, accompany by impaired neurogenesis of the dentate gyrus and decreased the number of neurons and area of grey mater, compared with the littermate controls. We further explored the molecular mechanisms underlying these changes, and found that Bmi-1 gene regulating proliferation related signal transduction pathways such as p16INK4 a and p27 were significantly increased in the hippocampus and cortex of Bmi-1+/- mice. The abnormal rate of mitochondria was also increased and mitochondrial energy metabolism related enzymes were decreased. The results suggested that the half-dose deletion of Bmi-1 gene inhibited the generation of new neurons in the hippocampus of the aged mice, resulting in the specific decreases in the hippocampal dentate gyrus volume, and the long-term memory dysfunction. This finding has provided the experimental theoretical basis for further exploring mechanisms of Bmi-1 gene regulating brain ageing and related anti-aging target in the future.