Renin-Angiotensin-System Increases Phosphorylated Tau and Reactive Oxygen Species in Human Cortical Neuron Cell Line

Alzheimer's Disease (AD) is the most common cause of dementia. AD patients had increased ex-tracellular amyloid β plaques and intracellular hyperphosphorylated tau (p-tau) in neurons. Re-cent studies have shown an association between the Renin-Angiotensin System (RAS) and AD. The involvement of RAS has been mediated through Angiotensin II (Ang II), which is overex-pressed in aging brains. However, the exact mechanism of how Ang II contributes to AD is un-known. Thus, we hypothesize that Ang II increases p-tau by activating its kinases, CDK5 and MAPK, and in-creases the production of Reactive Oxygen Species (ROS). In the human cortical neuron cell line, HCN2, treatment with Ang II upregulated the gene expression of CDK5 (2.9 folds, p<0.0001) and MAPTK (1.9 folds, p<0.001). The AT1R antagonist, Losartan, blocked the changes in tau kinases. Also, Ang II-induced the MAPK activation, increasing its phosphorylation by 400% (p<0.0001), an increase that was also blocked by Losartan. An increase in p-tau by Ang II was ob-served using fluorescent microscopy. We then quantified ROS production, and it was significantly increased by Ang II (p<0.01), and treatment with Losartan blunted their production (p<0.05). The data obtained demonstrated that Ang II might contribute to the pathogenesis of AD.

阿尔茨海默病（Alzheimer's Disease，简称 AD）系痴呆症的最常见病因。阿尔茨海默病患者脑神经元中存在增多的细胞外淀粉样β斑块及细胞内过度磷酸化的tau蛋白（p-tau）。近期研究揭示了肾素-血管紧张素系统（Renin-Angiotensin System，简称 RAS）与 AD 之间的关联。RAS 的作用是通过血管紧张素 II（Angiotensin II，简称 Ang II）介导的，该物质在老化的大脑中表达过度。然而，Ang II 如何导致 AD 的确切机制尚不明确。因此，我们提出假设：Ang II 通过激活其激酶 CDK5 和 MAPK，增加反应性氧物种（Reactive Oxygen Species，简称 ROS）的生成，从而提高 p-tau 的水平。在人类皮层神经元细胞系 HCN2 中，Ang II 处理上调了 CDK5（增加 2.9 倍，p<0.0001）和 MAPTK（增加 1.9 倍，p<0.001）的基因表达。AT1R 拮抗剂洛沙坦阻断了 tau 激酶的变化。此外，Ang II 诱导了 MAPK 的激活，使其磷酸化水平提高了 400%（p<0.0001），这一变化同样被洛沙坦所阻断。荧光显微镜观察到 Ang II 导致 p-tau 的增加。随后，我们量化了 ROS 的生成，发现 Ang II 显著增加了 ROS 的生成（p<0.01），而洛沙坦的处理则显著减弱了其生成（p<0.05）。所获得的数据表明，Ang II 可能会促进 AD 的发病机制。