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A Cdk5 inhibitor restores cognitive function and alleviates type 2 diabetes in mice

Sangita Paul1,2, Remya Chandran3, Dileep K Vijayan3

  • 1CSIR Institute of Genomics and Integrative Biology, New Delhi, India.

Iscience
|April 14, 2025
PubMed

Insights

New drugs targeting cyclin-dependent kinase 5 (Cdk5) show promise for treating cognitive decline in type 2 diabetes (T2D). These Cdk5 inhibitors improved glucose levels, obesity, and cognitive function in preclinical models.

Area of Science:

  • Neuroscience
  • Endocrinology
  • Pharmacology

Background:

  • Type 2 diabetes (T2D) is associated with cognitive decline and dementia risk.
  • Hyperglycemia and insulin dysregulation in T2D are linked to Alzheimer's disease (AD).
  • Dysregulated cyclin-dependent kinase 5 (Cdk5) activity is implicated in both T2D and AD pathology.

Purpose of the Study:

  • To identify therapeutic targets linking T2D and cognitive deterioration.
  • To discover novel brain-penetrant inhibitors of Cdk5 for potential T2D-related cognitive impairment treatment.

Main Methods:

  • Screening of the KINACore library to identify Cdk5 inhibitors.
  • Utilizing a high-fat diet-induced T2D mouse model.
  • Assessing the effects of identified inhibitors on metabolic parameters and cognitive function.

Main Results:

  • Two novel brain-penetrant Cdk5 inhibitors, BLINK11 and BLINK15, were discovered.
  • Treatment with these inhibitors improved blood glucose levels and reduced obesity in the T2D model.
  • Both inhibitors demonstrated efficacy in improving cognitive function in the preclinical model.

Conclusions:

  • Cdk5 is a key molecular link between T2D and cognitive decline.
  • BLINK11 and BLINK15 represent promising therapeutic candidates for T2D-associated cognitive impairment.
  • Targeting Cdk5 offers a potential therapeutic strategy for managing T2D and its neurological complications.
Keywords:
Biological sciencesEndocrinologyNatural sciencesNeurosciencePharmacologyPhysiology

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