Cognitive deficit is a prevalent and underestimated complication of diabetes, and the underlying cellular and molecular mechanisms are not well understood. Aberrant activity of
cyclin-dependent kinase (Cdk)5 is implicated in a number of
neurodegenerative diseases. The present study examined the role of Cdk5 in the progression of diabetes-related cognitive deficits. We showed that the
Cdk5 protein expression and
kinase activity were significantly increased in diabetic mice at 16 wk. In primary cultured hippocampal neurons exposed to 30 mM
glucose,
Cdk5 protein and
kinase activity were also elevated in a time-dependent manner. Moreover, the high
glucose exposure led to an aberrant Cdk5 activation due to its activator p25 that was cleaved from p35 by
calpain. Both in diabetic mice and in cultured hippocampal neurons exposed to high
glucose, inhibition of Cdk5 activity with
roscovitine (Ros) or
short hairpin RNA (
shRNA) decreased the
protein levels of cleaved
caspase-3 and the ratio of Bax and Bcl-2. The apoptotic rate detected by TUNEL in vivo or
Annexin V and
propidium iodide staining for flow cytometry in vitro also had obvious reduction. In addition, high
glucose exposure resulted in the increase of phosphorylated (phospho)-
MAPK kinase (MKK)6, phospho-p38, and c-Jun, which were rescued by Ros or Cdk5
shRNA. It is more important that the cognitive deficits of diabetic mice were also effectively alleviated by Ros. These results indicate that aberrant Cdk5 activity triggered hippocampal neuron apoptosis by activating MKK6/
p38 MAPK cascade in
hyperglycemia. Inhibition of Cdk5 overactivation attenuates neuronal apoptosis and cognitive deficits and contributes to the relief of diabetic neurotoxicity in the brain.-Liu, W., Zhou, Y., Liang, R., Zhang, Y. Inhibition of
cyclin-dependent kinase 5 activity alleviates diabetes-related cognitive deficits.