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Inhibition of cyclin‐dependent kinase 5 activity alleviates diabetes‐related cognitive deficits
Author(s) -
Liu Wei,
Zhou Yi,
Liang Rui,
Zhang Yue
Publication year - 2019
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.201901292r
Subject(s) - cyclin dependent kinase 5 , protein kinase a , kinase , p38 mitogen activated protein kinases , calpain , propidium iodide , small hairpin rna , endocrinology , apoptosis , microbiology and biotechnology , chemistry , biology , medicine , cyclin dependent kinase 2 , programmed cell death , gene knockdown , biochemistry , enzyme
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. FASEB J. 33, 14506‐14515 (2019). www.fasebj.org