Activation of α7 nicotinic acetylcholine receptor alleviates Aβ1-42-induced neurotoxicity via downregulation of p38 and JNK MAPK signaling pathways
Activation of α7 nicotinic acetylcholine receptor alleviates Aβ1-42-induced neurotoxicity via downregulation of p38 and JNK MAPK signaling pathways
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α7 烟碱乙酰胆碱受体的激活通过 p38 和 JNK MAPK 信号通路的下调减轻 Aβ1-42 诱导的神经毒性
DOI：
10.1016/j.neuint.2018.09.005
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发表时间：
2018-11-01
影响因子：
4.2
通讯作者：
Qian, Yi-Hua
中科院分区：
文献类型：
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作者：
Chang, Ke-Wei;Zong, Hang-Fan;Qian, Yi-Hua
淀粉样蛋白 β 肽 1-42 (A beta(1-42)) 可通过阿尔茨海默病 (AD) 中的氧化应激、炎症和神经元死亡诱导认知缺陷。 MAPK 通路被认为可介导 AD 中 A beta(1-42) 诱导的神经炎症反应、神经元死亡和认知能力下降。 α7 烟碱乙酰胆碱受体 (α7nAChR) 发挥神经保护作用。然而，a7nAChR 是否在体内通过 MAPK（p38、ERK、JNK）减轻 A beta(1-42) 诱导的神经毒性仍不清楚。在我们的研究中，使用 Y 迷宫测试评估了 C57BL/6 小鼠的记忆力。通过 Nissl 和 Hoechst 染色评估细胞死亡，并使用蛋白质印迹法评估 Bax、Bcl-2、Caspase 3 和细胞色素 C 水平。通过超氧化物歧化酶（SOD）、过氧化氢酶（CAT）和丙二醛（MDA）水平测定氧化应激。使用免疫组织化学法用 GFAP 和 Iba1 检查炎症。使用蛋白质印迹法测试 Aβ 降解酶、胰岛素降解酶 (IDE) 和脑啡肽酶 (NEP)。我们发现激活 α7nAChR 或抑制 p38 或 JNK 通路可通过减少氧化应激减轻 A beta(1-42) 诱导的认知缺陷以及神经元损失和死亡。此外，激活α7nAChR或抑制p38或JNK通路也能减轻炎症，观察到GFAP和Iba1水平降低，对AD降解酶有不同的影响。最后，我们发现α7nAChR的激活导致pp38和pJNK水平下调。相反，抑制 p38 或 JNK 会导致海马和皮质中 α7nAChR 水平上调。我们的数据表明，α 7nAChR 的激活减轻了 A beta(1-42) 诱导的神经毒性，这种保护作用可能通过 p38 和 JNK MAPK 的下调发挥作用。
Amyloid beta peptide 1-42 (A beta(1-42)) could induce cognitive deficits through oxidative stress, inflammation, and neuron death in Alzheimer's disease (AD). MAPK pathways have been thought to mediate A beta(1-42)-induced neuroinflammation responses, neuron death and cognitive decline in AD. The alpha 7 nicotinic acetylcholine receptor (alpha 7nAChR) exerts a neuroprotective effect. However, whether a7nAChR alleviates A beta(1-42) -induced neurotoxicity through MAPKs (p38, ERK, JNK) in vivo remains unclear. In our study, memory was assessed in C57BL/6 mice using a Y-maze test. Cell death was assessed by Nissl and Hoechst staining and Bax, Bcl-2, Caspase 3, and Cytochrome C levels using Western blotting. Oxidative stress was assayed by superoxide dismutase (SOD), catalase (CAT), and malondialdehyde (MDA) levels. Inflammation was examined with GFAP and Iba1 using immunohistochemistry. The A beta degrading enzymes insulin degrading enzyme (IDE) and neprilysin (NEP) were tested using Western blotting. We found that activating alpha 7nAChR or inhibiting p38 or JNK pathway alleviated A beta(1-42)-induced cognitive deficits and neuron loss and death by reducing oxidative stress. In addition, activating alpha 7nAChR or inhibiting p38 or JNK pathway also reduced inflammation, which was observed as reduced GFAP and Iba1 levels with different effects on AD degrading enzymes. Finally, we found that the activation of alpha 7nAChR led to the downregulation of pp38 and pJNK levels. Conversely, the inhibition of p38 or JNK resulted in the upregulation of alpha 7nAChR levels in the hippocampus and cortex. Our data indicate that the activation of alpha 7nAChR alleviates A beta(1-42)-induced neurotoxicity, and this protective effect might act through the down regulation of p38 and JNK MAPKs.