Cell Biology and Physiology Division, CSIR-Indian Institute of Chemical Biology, 4 Raja S. C. Mullick Road, Kolkata 700 032, India.
Cell Biology and Physiology Division, CSIR-Indian Institute of Chemical Biology, 4 Raja S. C. Mullick Road, Kolkata 700 032, India.
Mol Cell Neurosci. 2020 Oct;108:103551. doi: 10.1016/j.mcn.2020.103551. Epub 2020 Sep 5.
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.
星形胶质细胞激活是阿尔茨海默病（AD）的关键标志之一，与淀粉样β（Aβ）斑块、神经原纤维缠结和神经元死亡一起。神经胶质瘢痕和激活的星形胶质细胞分泌的因子对 AD 中的神经元健康有重要贡献。在这项研究中，我们研究了 AD 的体外和体内模型中星形胶质细胞激活的机制。在这方面，控制几种基本和应激相关细胞事件的丝裂原活化蛋白激酶（MAPK）信号级联已被牵连到各种神经疾病中的星形胶质细胞激活。我们通过 Western blot 和免疫细胞化学检查了不同 MAPK 的激活情况，发现 JNK 和 p38K 途径被激活，但 ERK 途径未被激活，在体外培养的 Aβ处理的星形胶质细胞和 Aβ输注的大鼠大脑皮层中均被激活。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后果，我们在存在和不存在 Aβ的情况下，分别用特异性抑制剂阻断这些途径，并检查 Aβ诱导的细胞增殖、形态变化和胶质纤维酸性蛋白（GFAP）上调。我们发现 JNK 和 p38K 信号级联的激活都参与了 Aβ诱导的星形胶质细胞增殖，而只有 p38K 途径参与了暴露于 Aβ的星形胶质细胞的形态变化和 GFAP 上调。为了进一步验证 p38K 途径在 Aβ诱导的星形胶质细胞激活中的作用，我们还观察到，转录因子 ATF2 是 p38 的下游磷酸化底物，在 Aβ处理后被磷酸化。综上所述，我们的研究表明，p38K 和 JNK 途径介导星形胶质细胞激活，两条途径都参与细胞增殖，但只有 p38K 途径参与 Aβ触发的形态变化。
