Department of Human Anatomy and Histology Embryology, Institute of Neurobiology, Key Laboratory of Environment and Genes Related to Diseases of Education Ministry, Xi'an Jiaotong University College of Medicine, 76, Yanta West Road, Xi'an 710061, Shaanxi, China.
Neurochem Int. 2012 Jul;61(2):227-35. doi: 10.1016/j.neuint.2012.04.019. Epub 2012 Apr 25.
The characteristic pathological change of Alzheimer's disease (AD) include deposits of β-amyloid protein (Aβ) in brain, neurofibrillary tangles (NFTs), as well as a few neuronal loss. Evidence shows that Aβ causes calcium influx and induces the cleavage of p35 into p25. Furthermore, the binding of p25 to cyclin-dependent kinase 5 (Cdk5) constitutively activates Cdk5. The p25/Cdk5 complex then hyperphosphorylates tau. Tanshinone IIA (tanIIA), a natural product extracted from Chinese herbal medicine Salvia miltiorrhiza BUNGE, has been reported to exert antioxidative activity. However, its neuroprotective activity remains unclear. The present study determined whether tanIIA protects neurons against Aβ(25-35)-induced cytotoxicity and detected the association of this protective effect with calpain and the p35/Cdk5 pathway. The results showed that tanIIA protected neurons against the neurotoxicity of Aβ(25-35), increased the viability of neurons, decreased expression of phosphorylated tau in neurons induced by Aβ(25-35), improved the impairment of the cell ultrastructure (such as nuclear condensation and fragmentation, and neurofibril collapse). Further more, we found that tanIIA maintained the normal expression of p35 on peripheral membranes, and decreased p25 expression in the cytoplasm. TanIIA also inhibited the translocation of Cdk5 from the nucleus into the cytoplasm of primary neurons induced by Aβ(25-35). These data suggested that tanIIA possessed neuroprotective action and the protection may involve in calpain and the p35/Cdk5 pathway.
阿尔茨海默病（AD）的特征性病理变化包括脑内β-淀粉样蛋白（Aβ）沉积、神经原纤维缠结（NFTs）以及少量神经元丢失。有证据表明，Aβ导致钙内流，并诱导 p35 分裂成 p25。此外，p25 与周期蛋白依赖性激酶 5（Cdk5）结合可使 Cdk5 持续激活。p25/Cdk5 复合物会使 tau 过度磷酸化。丹参酮 IIA（tanIIA）是从中药丹参中提取的天然产物，已被报道具有抗氧化活性。然而，其神经保护活性尚不清楚。本研究旨在确定 tanIIA 是否能保护神经元免受 Aβ（25-35）诱导的细胞毒性，并检测这种保护作用与钙蛋白酶和 p35/Cdk5 通路的关系。结果表明，tanIIA 可保护神经元免受 Aβ（25-35）的神经毒性，增加 Aβ（25-35）诱导的神经元活力，减少神经元中磷酸化 tau 的表达，改善细胞超微结构的损伤（如核浓缩和碎裂，神经原纤维崩溃）。此外，我们发现 tanIIA 可维持 p35 在胞外周膜的正常表达，并减少 Aβ（25-35）诱导的 p25 在细胞质中的表达。tanIIA 还可抑制 Aβ（25-35）诱导的 Cdk5 从细胞核向原代神经元细胞质的易位。这些数据表明，tanIIA 具有神经保护作用，这种保护可能涉及钙蛋白酶和 p35/Cdk5 通路。
