The Role And Mechanism Of Cyclin C In Alzheimer’s Disease

Alzheimer’s disease(AD)is a neurodegenerative disease that seriously threatens human health.There are three main pathological features of Alzheimer’s disease:amyloid plaque formed by deposition of extracellular amyloid protein,neurofibrillar tangle(NFT)formed by accumulation of highly phosphorylated tau protein in cells and brain atrophy.The most direct cause of AD is irreversible neuron death.Although AD has been discovered and studied for more than 100 years,there is still a lack of targeted AD prevention and treatment drugs.Therefore,it is urgent to discover and elucidate new pathogenic mechanisms and targets of AD.Cell cycle is a complex process involved in cell growth,cell proliferation,organ development and DNA damage repair regulation.Cell cycle involves many regulatory proteins,which can regulate the process of cell cycle together.The core of them is cyclin family and CDK family.Cyclin C can bind to cyclin dependent kinase 8(Cdk8)to induce phosphorylation of the carboxyl terminal domain of the large subunit of RNA polymerase Ⅱ to regulate RNA polymerase Ⅱ dependent transcription.Cyclin C can also bind to cyclin dependent kinase 3(Cdk3),which can stimulate PRB phosphorylation at S807/811 during G0/G1 transition and re-enter the cell cycle.It has been reported that the expression of Cyclin C is significantly increased in AD patients,but little is known about the role of Cyclin C in the nervous system,especially in the pathogenesis of AD.Our previous study found that the expression of Cyclin C and Cdk3 increased significantly in AD patients,and CyclinC/Cdk3 could induce tau protein phosphorylation.These results suggest that Cyclin C plays an important role in AD.Based on this,we systematically studied the effects of CyclinC on tau phosphorylation and neuronal survival by using Cyclin C knockout mice and Cyclin C overexpression virus.We found that overexpression of Cyclin C could significantly induce neuronal death and hippocampal atrophy in mice.As a Cyclin,Cyclin C can activate Cdk8 and Cdk3.However,there was a truncated mutation of Cdk3 in C57BL6 mice,and the protein could not be detected in mice,indicating that cyclin C may play a role through Cdk8.We also found that the activity of Cdk8 kinase was increased in AD mice,and abnormal high expression of Cyclin C could activate the activity of Cdk8 kinase.We speculate that Cyclin C/Cdk8 complex not only regulates gene transcription,but also participates in tau phosphorylation.We systematically studied the effect of Cyclin C/Cdk8 on tau phosphorylation.It was found that Cyclin C/Cdk8 could specifically phosphorylate TauS396 site.At the same time,p-tau(396)decreased significantly after Cyclin C knockdown.p-Tau(396)was also significantly inhibited by knockdown of Cyclin C expression in tau(P301S)mice.These results indicate that Cyclin C/Cdk8 complex has great effects on the pathogenesis of AD,especially in the regulation of tau phosphorylation.In conclusion,we revealed the relationship between Cyclin C and Alzheimer’s disease.The abnormal high expression of Cyclin C in AD can lead to the impairment of neuronal function,and can induce tau protein abnormal phosphorylation through Cdk3 and Cdk8,thus aggravating the disease process of AD.The results are helpful to understand the pathogenesis of AD and offer a new idea for the prevention and treatment of diseases based on tau phosphorylation.