P25/CDK5-mediated Tau Hyperphosphorylation in Both Ipsilateral and Contralateral Cerebra Contributes to Cognitive Deficits in Post-stroke Mice  

作　　者：Jing YU Yang ZHAO Xiao-kang GONG Zheng LIANG Yan-na ZHAO Xin LI Yu-ju CHEN You-hua YANG Meng-juan WU Xiao-chuan WANG Xi-ji SHU Jian BAO 

机构地区：[1]Institute of Biomedical Sciences,School of Medicine,Jianghan University,Wuhan,430056,China [2]Department of Pathology and Pathophysiology,School of Medicine,Jianghan University,Wuhan,430056,China [3]Department of Pathophysiology,School of Basic Medicine,Key Laboratory of Education Ministry of China for Neurological Disorders,Tongji Medical College,Huazhong University of Science and Technology,Wuhan,430030,China

出　　处：《Current Medical Science》2023年第6期1084-1095,共12页当代医学科学（英文）

基　　金：the National Natural Science Foundation of China(No.31800851);Natural Science Foundation of Hubei Province(No.2022CFB456);The Research Fund of Jianghan University(No.08210011).

摘　　要：Objective Post-stroke cognitive impairment(PSCI)develops in approximately one-third of stroke survivors and is associated with ingravescence.Nonetheless,the biochemical mechanisms underlying PSCI remain unclear.The study aimed to establish an ischemic mouse model by means of transient unilateral middle cerebral artery occlusions(MCAOs)and to explore the biochemical mechanisms of p25/cyclin-dependent kinase 5(CDK5)-mediated tau hyperphosphorylation on the PSCI behavior.Methods Cognitive behavior was investigated,followed by the detection of tau hyperphosphorylation,mobilization,activation of kinases and/or inhibition of phosphatases in the lateral and contralateral cerebrum of mice following ischemia in MACO mice.Finally,we treated HEK293/tau cells with oxygen-glucose deprivation(OGD)and a CDK5 inhibitor(Roscovitine)or a GSK3βinhibitor(LiCl)to the roles of CDK5 and GSK3βin mediating ischemia-reperfusion-induced tau phosphorylation.Results Ischemia induced cognitive impairments within 2 months,as well as causing tau hyperphosphorylation and its localization to neuronal somata in both ipsilateral and contralateral cerebra.Furthermore,p25 that promotes CDK5 hyperactivation had significantly higher expression in the mice with MCAO than in the shamoperation(control)group,while the expression levels of protein phosphatase 2(PP2A)and the phosphorylation level at Tyr307 were comparable between the two groups.In addition,the CDK5 inhibitor rescued tau from hyperphosphorylation induced by OGD.Conclusion These findings demonstrate that upregulation of CDK5 mediates tau hyperphosphorylation and localization in both ipsilateral and contralateral cerebra,contributing to the pathogenesis of PSCI.

关 键 词：cyclin-dependent kinase 5 p25 post-stroke cognitive impairment tau hyperphosphorylation 

分 类 号：R743.3[医药卫生—神经病学与精神病学]