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

IF 4.1 2区综合性期刊 Q1 MULTIDISCIPLINARY SCIENCES iScience Pub Date : 2025-04-18 Epub Date: 2025-03-11 DOI:10.1016/j.isci.2025.112200

Sangita Paul , Remya Chandran , Dileep K. Vijayan , Juhi Bhardwaj , Praveen Singh , Poornima Shetty , Srinivas Cheruku , Sajith Meleveetil , Binukumar Balachandran Krishnamma

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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.

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Cdk5抑制剂可恢复小鼠认知功能并减轻2型糖尿病

2型糖尿病（T2D）是一种代谢紊乱，通常与认知能力下降有关，增加了患者对痴呆的易感性。阿尔茨海默病（AD）与高血糖和胰岛素失调密切相关。有趣的是，某些抗糖尿病药物已经显示出减少t2d引起的认知障碍的潜力。之前的研究，包括我们的研究，都强调了周期蛋白依赖性激酶5 （Cdk5）活性在T2D和AD中的失调，这可能导致这些疾病的病理改变。因此，靶向Cdk5激酶可能为T2D和认知恶化提供一种治疗方法。我们的研究确定Cdk5是T2D和认知能力下降之间的关键联系。通过筛选KINACore文库，我们发现了两种新的脑渗透Cdk5抑制剂，BLINK11和BLINK15。在高脂肪饮食诱导的T2D模型中，这些抑制剂改善了血糖水平、肥胖和认知功能。尤其是BLINK11，有望成为治疗与T2D相关的认知障碍的候选药物。

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来源期刊

iScience Multidisciplinary-Multidisciplinary

CiteScore

7.20

自引率

1.70%

发文量

1972

审稿时长

6 weeks

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