Laboratory of Neuroscience, School of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile.
J Alzheimers Dis. 2012;32(2):417-29. doi: 10.3233/JAD-2012-120721.
Chronic neuroinflammation has been proposed as a driving force for Alzheimer's disease (AD), which is characterized by amyloid-β (Aβ) deposition, neurofibrillary tangles, neuronal loss, and activation of glial cells. Persistent activation of mitogen-activated protein kinases (MAPKs) and nuclear factor kappa B (NF-κB) pathway has been reported, which induces an increased expression of inflammatory mediators. Transforming growth factor β1 (TGFβ1) is an inflammation modulator whose levels are increased in AD. However, its canonical signaling pathway, Smad, appears to be impaired. Our previous findings indicate that TGFβ1 plays a key role in the pathogenesis of neuroinflammation, but the molecular mechanisms underlying its effects are not completely elucidated. Here, we studied the potential role of MKP-1, a phosphatase that exerts negative regulation on MAPK signaling, in the modulatory actions of TGFβ1. Using rat primary glial cultures, we found that pretreatment with TGFβ1 for 48 h reduced the production of inflammatory mediators induced by Aβ42, a result that was associated with prevention of MAPK p38 activation, attenuation of NF-κB p65 nuclear translocation, and an increase in MKP-1 levels. Moreover, suppression of MKP-1 expression by siRNA and inhibition of Smad3 reversed the modulation of inflammatory response exerted by TGFβ1. These results indicate that TGFβ1 induces the expression of MKP-1 in glial cells through the Smad pathway and inhibits MAPK and NF-κB signaling, thus revealing a novel mechanism for the neuroprotective actions of TGFβ1. Further research would be important in order to characterize the role of this mechanism in the pathogenesis of AD.
慢性神经炎症被认为是阿尔茨海默病（AD）的驱动因素，其特征是淀粉样β（Aβ）沉积、神经原纤维缠结、神经元丧失和神经胶质细胞激活。已经报道了丝裂原活化蛋白激酶（MAPKs）和核因子 kappa B（NF-κB）途径的持续激活，这会诱导炎症介质的表达增加。转化生长因子β1（TGFβ1）是一种炎症调节剂，其水平在 AD 中增加。然而，其经典信号通路 Smad 似乎受损。我们之前的研究结果表明，TGFβ1 在神经炎症发病机制中发挥关键作用，但尚不完全清楚其作用的分子机制。在这里，我们研究了 MKP-1（一种对 MAPK 信号起负调控作用的磷酸酶）在 TGFβ1 调节作用中的潜在作用。使用大鼠原代神经胶质细胞培养物，我们发现 TGFβ1 预处理 48 h 可减少 Aβ42 诱导的炎症介质产生，这与 MAPK p38 激活的预防、NF-κB p65 核易位的减弱以及 MKP-1 水平的增加有关。此外，siRNA 抑制 MKP-1 表达和 Smad3 抑制逆转了 TGFβ1 对炎症反应的调节。这些结果表明，TGFβ1 通过 Smad 途径诱导神经胶质细胞中 MKP-1 的表达，并抑制 MAPK 和 NF-κB 信号，从而揭示了 TGFβ1 的神经保护作用的新机制。进一步的研究对于确定该机制在 AD 发病机制中的作用非常重要。
