Zhang G-R, Cheng X-R, Zhou W-X, Zhang Y-X
Department of Neuroimmunopharmacology, Beijing Institute of Pharmacology and Toxicology, 27 Taiping Road, Beijing 100850, China.
Neuroscience. 2009 Mar 3;159(1):308-15. doi: 10.1016/j.neuroscience.2008.06.068. Epub 2008 Jul 25.
Senescence-accelerated mouse (SAM) prone/8 (SAMP8) is a good animal model to investigate the fundamental mechanisms of age-related learning and memory deficits such as Alzheimer's disease (AD) at the gene and protein levels, and SAM resistant/1 (SAMR1) is its normal control. Calcium/calmodulin-dependent protein kinase II-alpha (CaMKIIalpha) is one of the most abundant subunits of calcium/calmodulin-dependent protein kinase II in cerebral cortex and hippocampus, and is closely linked to AD. In this study, we used real time fluorescence quantitative PCR (RT-PCR) and Western blot techniques to examine the expression of CaMKIIalpha mRNA and protein in the cerebral cortex and hippocampus of SAMP8 both with aging and following treatment with anti-AD drugs (for example, natural product huperzine A (HupA) and traditional Chinese medicinal prescription Liu-Wei-Di-Huang decoction (LW), Ba-Wei-Di-Huang decoction (BW), Huang-Lian-Jie-Du decoction (HL), Dang-Gui-Shao-Yao-San (DSS) and Tiao-Xin-Fang decoction (TXF)). The results showed that the levels of both CaMKIIalpha mRNA and protein decreased significantly in the cerebral cortex of SAMR1 with aging, but increased significantly in the cerebral cortex of SAMP8. Compared with age-matched SAMR1, the expression of mRNA and protein of CaMKIIalpha significantly increased in the cerebral cortex and hippocampus of SAMP8 after 10 months of age. After SAMP8 was treated with the previously mentioned drugs, the abnormally high expression of CaMKIIalpha was relatively down-regulated. These results indicated that the expression of CaMKIIalpha in the brain of SAMP8 was abnormal and that this abnormality could be reversed with anti-AD drugs. These data suggest that CaMKIIalpha may play an important role in the age-related cognitive deterioration in AD, and may be a potential targets for anti-AD drugs.
衰老加速小鼠（SAM）易感性/8（SAMP8）是一种良好的动物模型，可在基因和蛋白质水平研究与年龄相关的学习和记忆缺陷（如阿尔茨海默病（AD））的基本机制，而SAM抗性/1（SAMR1）是其正常对照。钙/钙调蛋白依赖性蛋白激酶II-α（CaMKIIα）是大脑皮层和海马中钙/钙调蛋白依赖性蛋白激酶II最丰富的亚基之一，与AD密切相关。在本研究中，我们使用实时荧光定量PCR（RT-PCR）和蛋白质免疫印迹技术检测了衰老的SAMP8以及用抗AD药物（如天然产物石杉碱甲（HupA）和中药方剂六味地黄丸（LW）、八味地黄丸（BW）黄连解毒汤（HL）、当归芍药散（DSS）和调心方（TXF））治疗后的大脑皮层和海马中CaMKIIα mRNA和蛋白质的表达。结果显示，随着年龄增长，SAMR1大脑皮层中CaMKIIα mRNA和蛋白质水平均显著下降，但SAMP8大脑皮层中则显著升高。与年龄匹配的SAMR1相比，10月龄后SAMP8大脑皮层和海马中CaMKIIα的mRNA和蛋白质表达显著增加。SAMP8用上述药物治疗后，CaMKIIα的异常高表达相对下调。这些结果表明，SAMP8大脑中CaMKIIα的表达异常，且这种异常可被抗AD药物逆转。这些数据表明，CaMKIIα可能在AD中与年龄相关的认知衰退中起重要作用，可能是抗AD药物的潜在靶点。
