The Regulation Of CDK3and Its Relevance In The Pathogenesis Of Alzheimer’s Disease

Alzheimer’s Disease (AD) is a progressive neurodegenerative disorder of the central nervous system characterized by progressive cognitive impairment and memory loss. Two main pathologic features of AD are extracellular deposition of the amyloid β peptide(AP) formed senile plaques and intracellular neurofibrillary tangles(NFT) consisting of hyperphosphorylated microtubule-associated tau. The absence of neuronal death is the ultimate cause of AD, the study of mechanisms of neuronal apoptosis in AD has been a hotspot in this field. As the non-renewable nature of neurons, neuronal death will not make up for once and save. Recent studies show that the pathogenesis of AD is accompanied by neuronal cell cycle re-activation. If the post-mitotic neurons reenter the cell cycle,the ending leads to die instead of dividing. Cyclin-dependent kinase3(Cyclin-dependent Kinases3, CDK3) was activated by protein Cyclin C and then can induce cell cycle transition from quiescent (GO) to re-enter the cell cycle.The first step of reactivation cycle in the AD post-mitotic neurons is G0/G1phase progression. So CDK3and CyclinC may reactivate AD neuronal cell cycle. Our preliminary results identified that CDK3and CyclinC are dramatically increased in the brains of AD patients compared with age-matched non-AD patients’. And active CDK3has the capability to phosphorylate tau at T181site. These data suggested that CDK3is a potential target for pharmatheutical approach in AD. In the current study, we next discuss regulatory mechanism of CDK3by protein stability and mRNA transcription. We found protein and mRNA level of CDK3oscillate during cell cycle and occurred peaks before entering S phase. This result suggests that the high level of CDK3is needed for cell to enter S phase during cell cycle. We next explore whether the protein stability of CDK3is involved in the proteins regulation during cell cycle progression, the preliminary findings demonstrates that the ubiquitination of CDK3did not cause its’ obvious degradation, but after the suppression of the lysosomal pathway can inhibit protein degradation CDK3to some extent. We also constructed a promoter of CDK3to study the regulation of transcription levels by luciferase reporter, and found that the CDK3transcriptional activity was significantly increased before the S phase. Next, we performed a serial truncated mutantions of CDK3promoter region to initially speculate that P53etc may be transcription factors that regulated CDK3.From the above study, we investigated that transcriptional and post-transcriptioinal regulation of CDK3during cell cycle progression. Since CDK3plays a very important role in the potential activation of neuronal cell cycle in Alzheimer’s disease, the study of this subject provides a theoretical and experimental basis to better understand the mechanism of CDK3activating neuronal cell cycle and neuronal apoptosis. The current study also provides a potential target for the prevention and treatment of Alzheimer’s research.