Activation of Cdk5/p25 and tau phosphorylation following chronic brain hypoperfusion in rats involves microRNA-195 down-regulation
Li-Hua Sun, Tao Ban, Cheng-Di Liu, Qing-Xin Chen, Xu Wang, Mei-Ling Yan, Xue-Ling Hu, Xiao-Lin Su, Ya-Nan Bao, Lin-Lin Sun, Lin-Jing Zhao, Shuang-Chao Pei, Xue-Mei Jiang, De-Kang Zong and Jing Ai
Article first published online: 7 AUG 2015 | DOI: 10.1111/jnc.13212
Schematic diagram of miR-195 mediated Aβ aggregation and tau hyperphosphorylation in chronic brain hypoperfusion (CBH). First, CBH results in the elevation of nuclear factor-κB (NF-κB), which binds with the promoter sequences of miR-195 and negatively regulates the expression of miR-195. Second, down-regulated miR-195 induces up-regulation of APP and BACE1 and leads to an increase in Aβ levels. Third, some of the elevated Aβ then enter the intracellular space and activate calpain, which promotes the conversion of Cdk5/p35 to Cdk5/p25 and catalyzes the degradation of IκB; IκB is an inhibitor of NF-κB, which activates NF-κB. Cdk5/p25 directly phosphorylates Tau. Fourth, down-regulated miR-195 induces an up-regulation of p35, which provides the active substrates of p25. Our findings demonstrated that the down-regulation of miR-195 plays a key role in the increased vulnerability to dementia via the regulation of multiple targets following CBH.