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

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.