Okadaic acid induced cyclin B1 expression and mitotic catastrophe in rat cortex.
Accumulating evidence indicates that the aberrant re-entry of post-mitotic neurons into the G2/M phase of cell cycle and the resulting mitotic catastrophe may contribute to the pathogenesis of Alzheimer's disease. However, the cellular event that drives the differentiated neurons to abnormally enter G2/M phase remains elusive. Similarly, whether mitotic catastrophe is indeed one of the death pathways for differentiated neurons is not clear. Previous studies revealed that okadaic acid (OA), a phosphatase inhibitor that induces AD like pathological changes, evokes mitotic changes in neuroblastoma cells. In this study, we examined the in vivo effects of OA on cyclin B1 expression, the induction of mitosis, and subsequent mitotic catastrophe. We found that cyclin B1 expression in adult neurons was significantly increased after injecting OA into rat frontal cortex, which also increased tau protein phosphorylation. Interestingly, cyclin B1 and phosphorylated tau were well co-localized around the OA injection site, but were only partially co-localized in other brain regions. Staining with toluidine blue, Giemsa dye or propidium iodide revealed typical mitotic and mitotic catastrophe-like morphological changes with irregular arrangement of condensed chromatin and chromosome fibers in a few cells. Furthermore, the strong cyclin B1 staining in these cells suggests that cyclin B1 promoted G2 to M phase transition is required for the mitotic catastrophe. The detection of neuron-specific enolase in a portion of these cells demonstrated that at least part them are neuron. All together, our results suggest that the disturbance of the protein kinase-phosphatase system caused by OA is sufficient to induce neuronal cyclin B1 expression, force neurons into the mitotic phase of cell cycle, and cause mitotic catastrophe.
Chen
Bo
B
National Laboratory of Medical Neurobiology, Shanghai Medical College, Fudan University, Shanghai, PR China.
Cheng
Min
M
Hong
Dao-Jun
DJ
Sun
Feng-Yan
FY
Zhu
Cui-Qing
CQ
D000818:Animals; D015153:Blotting, Western / Q000379:methods; D002540:Cerebral Cortex / Q000187:drug effects*; D019926:Cyclin B / Q000378:metabolism*; D056744:Cyclin B1; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005455:Fluorescent Antibody Technique / Q000379:methods; D005786:Gene Expression Regulation / Q000187:drug effects*; D008297:Male; D008938:Mitosis / Q000187:drug effects*; D019319:Okadaic Acid / Q000494:pharmacology*; D010751:Phosphopyruvate Hydratase / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors; D016875:tau Proteins / Q000378:metabolism
C534701:Ccnb1 protein, rat; D019926:Cyclin B; D056744:Cyclin B1; D004791:Enzyme Inhibitors; D016875:tau Proteins; D019319:Okadaic Acid; D010751:Phosphopyruvate Hydratase