2024(11):1473-1482,1516.
DOI: 10.7655/NYDXBNSN240836
Abstract:
Objective:B-cell specific moloney leukemia virus insertion site 1(Bmi-1)has been extensively documented for its role in stem cell proliferation and differentiation,but its role in the brain of aged mice remains unclear. The study aimed to investigate the pathophysiological role of Bmi-1 in brain aging. Methods:Seventeen-month-old Bmi-1 heterozygous(Bmi-1 +/-)mice and wild-type (WT)mice were selected as experimental subjects. Behavioral testing,immunohistochemistry,and Masson staining techniques were used to compared the overall health status and long-term memory abilities of Bmi-1 +/- mice with WT mice. HE staining,electron microscopy,and Western blot were emplyed to investigate the potential effects of Bmi-1 gene haploinsufficiency on the brain aging in mice. Results:Compared with the WT mice,Bmi-1 +/- mice showed a diminished long-term spatial memory function(P < 0.05), accompanied by a reduction in neurogenesis in the hippocampal dentate gyrus(DG,P < 0.05),a decrease in neuronal numbers(P < 0.05),and a reduction in the grey matter volume(P < 0.05). Further studies revealed that compared with the WT mice,Bmi-1+/- mice exhibited enlarged and swollen mitochondria in DG neurons,with an increased proportion of reduced mitochondrial cristae(P < 0.05), and a significant increase in the number of lipofuscin in the cytoplasm of DG neurons(P < 0.05). Additionally,the expression levels of mitochondrial energy metabolism-related proteins,such as NADH dehydrogenase(ubiquinone)flavoprotein 2(NDUFV2)and NADH dehydrogenase(ubiquinone)ferrithionein 3(NDUFS3),were down-regulated in the DG region of Bmi-1+/- mice(P < 0.05),and the key catalytic enzyme dihydrolipoyl S-succinyltransferase(DLST)in the tricarboxylic acid cycle was also significantly down-regulated(P < 0.01). Meanwhile,among the cell cycle factors regulated by Bmi -1,the cyclin -dependent kinase inhibitor p27 and oncoprotein p53 were significantly up-regulated(P < 0.05). Conclusion:Half dose deletion of the Bmi-1 gene inhibits the generation of new neurons in the hippocampal region of aged mice,leading to a specific reduction in the volume of the hippocampal DG region and impairments in long -term memory function. The underlying mechanism may be related to the abnormal expression of aging-related proteins p27 and p53,as well as neuronal mitochondrial degeneration.