Astrocyte activation is one of the crucial hallmarks of Alzheimer's disease (AD) along with amyloid-β (Aβ) plaques, neurofibrillary tangles and neuron death. Glial scar and factors secreted from activated astrocytes have important contribution on neuronal health in AD. In this study, we investigated the mechanisms of astrocyte activation both in in vitro and in vivo models of AD. In this regard, mitogen activated protein kinase (MAPK) signalling cascades that control several fundamental and stress related cellular events, has been implicated in astrocyte activation in various neurological diseases. We checked activation of different MAPKs by western blot and immunocytochemistry and found that both JNK and p38K, but not ERK pathways are activated in Aβ-treated astrocytes in culture and in Aβ-infused rat brain cortex. Next, to investigate the downstream consequences of these two MAPKs (JNK and p38K) in Aβ-induced astrocyte activation, we individually blocked these pathways by specific inhibitors in presence and absence of Aβ and checked Aβ-induced cellular proliferation, morphological changes and glial fibrillary acidic protein (GFAP) upregulation. We found that activation of both JNK and p38K signalling cascades are involved in astrocyte proliferation evoked by Aβ, whereas only p38K pathway is implicated in morphological changes and GFAP upregulation in astrocytes exposed to Aβ. To further validate the implication of p38K pathway in Aβ-induced astrocyte activation, we also observed that transcription factor ATF2, a downstream phosphorylation substrate of p38, is phosphorylated upon Aβ treatment. Taken together, our study indicates that p38K and JNK pathways mediate astrocyte activation and both the pathways are involved in cellular proliferation but only p38K pathway contributes in morphological changes triggered by Aβ.

星形胶质细胞活化是阿尔茨海默氏病（AD）的重要标志之一，同时还有淀粉样β（Aβ）斑块，神经原纤维缠结和神经元死亡。胶质瘢痕和活化星形胶质细胞分泌的因子对AD的神经元健康有重要贡献。在这项研究中，我们研究了体外和体内星形胶质细胞激活的机制AD的模型。在这方面，控制多种基本和与压力相关的细胞事件的促分裂原活化蛋白激酶（MAPK）信号级联反应已与多种神经系统疾病中的星形胶质细胞活化有关。我们通过蛋白质印迹和免疫细胞化学检查了不同MAPK的激活，发现在培养物中经Aβ处理的星形胶质细胞和注入Aβ的大鼠大脑皮层中均激活了JNK和p38K，但未激活ERK途径。接下来，为了研究这两种MAPK（JNK和p38K）在Aβ诱导的星形胶质细胞激活中的下游影响，我们通过存在和不存在Aβ的特异性抑制剂分别阻断了这些途径，并检查了Aβ诱导的细胞增殖，形态学改变和神经胶质原纤维酸性蛋白（GFAP）上调。我们发现JNK和p38K信号级联反应的激活均与Aβ引起的星形胶质细胞增殖有关，而只有p38K途径与暴露于Aβ的星形胶质细胞的形态变化和GFAP上调有关。为了进一步验证p38K途径在Aβ诱导的星形胶质细胞活化中的作用，我们还观察到转录因子ATF2（p38的下游磷酸化底物）在Aβ处理后被磷酸化。两者合计，我们的研究表明p38K和JNK通路介导星形胶质细胞激活，这两个通路均参与细胞增殖，但只有p38K通路参与Aβ触发的形态变化。为了进一步验证p38K途径在Aβ诱导的星形胶质细胞活化中的作用，我们还观察到转录因子ATF2（p38的下游磷酸化底物）在Aβ处理后被磷酸化。两者合计，我们的研究表明p38K和JNK通路介导星形胶质细胞活化，并且这两种通路均参与细胞增殖，但只有p38K通路参与Aβ触发的形态变化。为了进一步验证p38K途径在Aβ诱导的星形胶质细胞活化中的作用，我们还观察到转录因子ATF2（p38的下游磷酸化底物）在Aβ处理后被磷酸化。两者合计，我们的研究表明p38K和JNK通路介导星形胶质细胞激活，这两个通路均参与细胞增殖，但只有p38K通路参与Aβ触发的形态变化。