Departamento de Farmacologia, Universidade Federal de Santa Catarina, Santa Catarina, Brazil.
Behav Brain Res. 2010 May 1;209(1):165-73. doi: 10.1016/j.bbr.2010.01.040. Epub 2010 Feb 1.
Alzheimer's disease (AD), a chronic degenerative and inflammatory brain disorder characterized by neuronal dysfunction and loss, is linked to accumulation of beta-amyloid (Abeta) peptide. Tumor necrosis factor-alpha (TNF-alpha) and cyclooxygenase-2 (COX-2) are proteins that have key roles in immune cell activation, inflammation and cognitive function in the brain. Here, we evaluated the link between TNF-alpha and COX-2 on the acute responses elicited by Abeta. Behavioral and molecular analyses were performed in mice after an intracerebroventricular (i.c.v.) injection of Abeta(1-40). Genetic and/or pharmacological approaches were used to inhibit TNF-alpha and COX-2. I.c.v. Abeta(1-40) injection in mice activates TNF-alpha signaling pathway resulting in COX-2 upregulation, synaptic loss and cognitive decline. Pharmacological studies revealed that COX-2 is involved in the cognitive impairment mediated by TNF-alpha. However, COX-2 inhibition failed in reducing the synaptophysin loss induced by Abeta(1-40). The COX-2 upregulation induced by Abeta(1-40) was attributed to activation of different protein kinases and transcriptional factors that are greatly regulated by TNF-alpha. Together, these results indicate that Abeta(1-40) induces the activation of several TNF-alpha-dependent intracellular signaling pathways that play a key role in the control of COX-2 upregulation and activation, synaptic loss and cognitive decline in mice. Therefore, selective TNF-alpha inhibitors may be potentially interesting tools for AD drug development.
阿尔茨海默病（AD）是一种慢性进行性和炎症性脑疾病，其特征为神经元功能障碍和丧失，与β-淀粉样肽（Abeta）的积累有关。肿瘤坏死因子-α（TNF-α）和环氧化酶-2（COX-2）是在免疫细胞激活、炎症和大脑认知功能中起关键作用的蛋白质。在这里，我们评估了 TNF-α和 COX-2 与 Abeta 引起的急性反应之间的联系。在 Abeta(1-40)脑室内注射后，对小鼠进行行为和分子分析。使用遗传和/或药理学方法抑制 TNF-α和 COX-2。Abeta(1-40)脑室内注射在小鼠中激活 TNF-α信号通路，导致 COX-2 上调、突触丧失和认知下降。药理学研究表明 COX-2 参与了 TNF-α介导的认知障碍。然而，COX-2 抑制未能减少 Abeta(1-40)诱导的突触小泡蛋白丢失。Abeta(1-40)诱导的 COX-2 上调归因于不同蛋白激酶和转录因子的激活，这些激酶和转录因子受 TNF-α的调节。总之，这些结果表明 Abeta(1-40)诱导了几种依赖 TNF-α的细胞内信号通路的激活，这些信号通路在控制 COX-2 上调和激活、突触丧失和小鼠认知下降方面发挥着关键作用。因此，选择性 TNF-α抑制剂可能是 AD 药物开发的潜在有前途的工具。
