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

  • iScience. 2025 Mar 11;28(4):112200. doi: 10.1016/j.isci.2025.112200.
Sangita Paul  1  2 ,  Remya Chandran  3 ,  Dileep K Vijayan  3 ,  Juhi Bhardwaj  1  2 ,  Praveen Singh  1  2 ,  Poornima Shetty  4 ,  Srinivas Cheruku  5 ,  Sajith Meleveetil  6 ,  Binukumar Balachandran Krishnamma  1  2
Affiliations
  • 1. CSIR Institute of Genomics and Integrative Biology, New Delhi, India.
  • 2. Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India.
  • 3. Laboratory for Computational and Structural Biology, Jubilee Centre for Medical Research, Jubilee Mission Medical College and Research Institute, Thrissur 680005, Kerala, India.
  • 4. Srinivasa Engineering College, Mukka, Mangalore 574146, India.
  • 5. Department of Chemistry, Manasa Gangotri, Mysore University, Mysuru 570005, India.
  • 6. Department of Chemistry, SSIT, Sri Siddhartha Academy of Higher Education, Tumkur 572107, Karnataka, India.
PMID: 40224020 DOI: 10.1016/j.isci.2025.112200
Abstract

Type 2 diabetes (T2D) is a metabolic disorder commonly linked with cognitive decline, increasing patients' susceptibility to dementia. Alzheimer's disease (AD) has a strong connection with hyperglycemia and Insulin dysregulation. Interestingly, certain anti-diabetic drugs have shown potential in reducing T2D-induced cognitive impairment. Previous studies, including ours, have highlighted the dysregulation of cyclin-dependent kinase 5 (CDK5) activity in both T2D and AD, which may contribute to pathological changes in these conditions. Thus, targeting the CDK5 kinase could offer a therapeutic approach for T2D and cognitive deterioration. Our research identifies CDK5 as a key link between T2D and cognitive decline. By screening the KINACore library, we discovered two new brain-penetrant CDK5 inhibitors, BLINK11 and BLINK15. In a high-fat diet-induced T2D model, these inhibitors improved blood glucose levels, obesity, and cognitive function. BLINK11, in particular, shows promise as a therapeutic candidate for treating cognitive impairment associated with T2D.

Keywords
Biological sciences; Endocrinology; Natural sciences; Neuroscience; Pharmacology; Physiology.
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