Anti-diabetes drug pioglitazone ameliorates synaptic defects in AD transgenic mice by inhibiting cyclin-dependent kinase5 activity.
Anti-diabetes drug pioglitazone ameliorates synaptic defects in AD transgenic mice by inhibiting cyclin-dependent kinase5 activity.
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DOI：
10.1371/journal.pone.0123864
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发表时间：
2015
期刊：
影响因子：
3.7
通讯作者：
Li J
中科院分区：
文献类型：
--
作者：
Chen J;Li S;Sun W;Li J
细胞周期蛋白依赖性激酶 5 (Cdk5) 是一种丝氨酸/苏氨酸激酶，由神经元特异性激活剂 p35/p39 激活，在神经元发育中发挥许多重要作用。然而，Cdk5 的异常激活被认为与多种神经退行性疾病的发病机制有关，包括阿尔茨海默病 (AD) 和帕金森病 (PD)。在本研究中，在 AD 小鼠模型中观察到 Cdk5 活性增强；而可溶性β淀粉样蛋白寡聚体（Aβ）会导致AD发病过程中的突触衰竭，并在培养的海马神经元中诱导Cdk5过度激活。通过药理学或遗传学方法抑制 Cdk5 活性可逆转可溶性淀粉样蛋白-β 寡聚物 (Aβ) 治疗引起的树突棘损失。有趣的是，我们发现抗糖尿病药物吡格列酮可以通过降低p35蛋白水平来抑制Cdk5活性。更重要的是，吡格列酮治疗纠正了培养切片中 Aβ 暴露引起的长时程增强 (LTP) 缺陷，并且吡格列酮给药挽救了 AD 小鼠模型中受损的 LTP 和空间记忆。总而言之，我们的研究描述了吡格列酮在缓解 AD 方面的意想不到的作用，并揭示了一种治疗 AD 的潜在治疗药物。
Cyclin-dependent kinase 5 (Cdk5) is a serine/threonine kinase that is activated by the neuron specific activators p35/p39 and plays many important roles in neuronal development. However, aberrant activation of Cdk5 is believed to be associated with the pathogenesis of several neurodegenerative diseases, including Alzheimer’s disease (AD) and Parkinson’s disease (PD). Here in the present study, enhanced Cdk5 activity was observed in mouse models of AD; whereas soluble amyloid-β oligomers (Aβ), which contribute to synaptic failures during AD pathogenesis, induced Cdk5 hyperactivation in cultured hippocampal neurons. Inhibition of Cdk5 activity by pharmacological or genetic approaches reversed dendritic spine loss caused by soluble amyloid-β oligomers (Aβ) treatment. Interestingly, we found that the anti-diabetes drug pioglitazone could inhibit Cdk5 activity by decreasing p35 protein level. More importantly, pioglitazone treatment corrected long-term potentiation (LTP) deficit caused by Aβ exposure in cultured slices and pioglitazone administration rescued impaired LTP and spatial memory in AD mouse models. Taken together, our study describes an unanticipated role of pioglitazone in alleviating AD and reveals a potential therapeutic drug for AD curing.
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