A Cdk5 inhibitory peptide reduces tau hyperphosphorylation and apoptosis in neurons
A Cdk5 inhibitory peptide reduces tau hyperphosphorylation and apoptosis in neurons
复制标题
DOI：
10.1038/sj.emboj.7600441
复制
发表时间：
2005-01-12
期刊：
影响因子：
11.4
通讯作者：
Pant, HC
中科院分区：
文献类型：
--
作者：
Zheng, YL;Kesavapany, S;Pant, HC
淀粉样蛋白β (Abeta)肽的细胞外聚集和特定表位上tau蛋白的细胞内过度磷酸化是神经退行性疾病（如阿尔茨海默病（AD））的病理标志。当Cdk5与p25结合时，可磷酸化AD特异性磷酸化表位上的tau蛋白。p25是一种截断的激活因子，由暴露于β肽的生理Cdk5激活因子p35产生。我们发现Cdk5抑制肽（CIP）的神经元感染选择性地抑制p25/ Cdk5活性并抑制皮质神经元中异常的tau磷酸化。此外，与CIP共感染后，Abeta(1-42)-诱导的皮质神经元凋亡也减少。特别重要的是，我们发现CIP不会抑制内源性或转染的p35/ Cdk5活性，也不会抑制其他细胞周期蛋白依赖性激酶，如Cdc2， Cdk2， Cdk4和Cdk6。因此，这些结果提供了一种策略，可以解决并可能改善神经退行性疾病的病理，这些疾病可能是p25异常激活Cdk5的结果，而不影响正常的Cdk5活性。
The extracellular aggregation of amyloid beta (Abeta) peptides and the intracellular hyperphosphorylation of tau at specific epitopes are pathological hallmarks of neurodegenerative diseases such as Alzheimer's disease ( AD). Cdk5 phosphorylates tau at AD- specific phospho- epitopes when it associates with p25. p25 is a truncated activator, which is produced from the physiological Cdk5 activator p35 upon exposure to Abeta peptides. We show that neuronal infections with Cdk5 inhibitory peptide ( CIP) selectively inhibit p25/ Cdk5 activity and suppress the aberrant tau phosphorylation in cortical neurons. Furthermore, Abeta(1-42)- induced apoptosis of these cortical neurons was also reduced by coinfection with CIP. Of particular importance is our finding that CIP did not inhibit endogenous or transfected p35/ Cdk5 activity, nor did it inhibit the other cyclin- dependent kinases such as Cdc2, Cdk2, Cdk4 and Cdk6. These results, therefore, provide a strategy to address, and possibly ameliorate, the pathology of neurodegenerative diseases that may be a consequence of aberrant p25 activation of Cdk5, without affecting ' normal' Cdk5 activity.