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Inhibition of cyclin-dependent kinase 5 activity alleviates diabetes-related cognitive deficits

Wei Liu1, Yi Zhou2, Rui Liang1

  • 1Department of Pathology, The Second Hospital of Hebei Medical University, Hebei Medical University, Shijiazhuang, China.

FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology
|November 6, 2019
PubMed

Insights

Diabetic cognitive deficits are linked to increased cyclin-dependent kinase 5 (Cdk5) activity. Inhibiting Cdk5 reduces neuronal apoptosis and improves cognitive function in diabetic mice, offering a potential therapeutic target.

Area of Science:

  • Neuroscience
  • Endocrinology
  • Molecular Biology

Background:

  • Diabetes mellitus is associated with cognitive deficits, but underlying mechanisms remain unclear.
  • Aberrant cyclin-dependent kinase 5 (Cdk5) activity is implicated in neurodegenerative diseases.
  • The role of Cdk5 in diabetes-related cognitive impairment requires further investigation.

Purpose of the Study:

  • To investigate the role of Cdk5 in the development of cognitive deficits in diabetes.
  • To explore the molecular mechanisms by which Cdk5 contributes to neuronal damage in hyperglycemia.
  • To evaluate the therapeutic potential of inhibiting Cdk5 activity in diabetic cognitive impairment.

Main Methods:

  • Diabetic mouse model and primary cultured hippocampal neurons exposed to high glucose.
  • Assessment of Cdk5 protein expression, kinase activity, and activation by its cofactor p25.
  • Inhibition of Cdk5 using roscovitine (Ros) or short hairpin RNA (shRNA).
  • Evaluation of apoptosis markers (caspase-3, Bax/Bcl-2 ratio, TUNEL, Annexin V/propidium iodide staining).
  • Analysis of the MKK6/p38 MAPK signaling pathway.
  • Behavioral testing to assess cognitive function in diabetic mice.

Main Results:

  • Cdk5 protein expression and kinase activity were significantly elevated in diabetic mice and high glucose-treated neurons.
  • High glucose induced aberrant Cdk5 activation via p25 cleavage by calpain.
  • Cdk5 inhibition reduced neuronal apoptosis by decreasing cleaved caspase-3 and altering Bax/Bcl-2 ratio.
  • Cdk5 inhibition attenuated the activation of the MKK6/p38 MAPK pathway.
  • Treatment with roscovitine significantly alleviated cognitive deficits in diabetic mice.

Conclusions:

  • Aberrant Cdk5 activity in hyperglycemia promotes hippocampal neuron apoptosis through the MKK6/p38 MAPK cascade.
  • Inhibition of Cdk5 overactivation mitigates neuronal apoptosis and cognitive deficits.
  • Targeting Cdk5 offers a promising strategy for treating diabetic neurotoxicity and cognitive impairment.
Keywords:
apoptosisdiabetes mellitushippocampus

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