Department of Human Anatomy, Histology and Embryology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, 76 Yanta West Road, Xi'an, 710061, China.
Department of Human Anatomy, Histology and Embryology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, 76 Yanta West Road, Xi'an, 710061, China; Key Laboratory of Environment and Genes Related to Diseases (Xi'an Jiaotong University), Ministry of Education of China, Xi'an Jiaotong University Health Science Center, 76 Yanta West Road, Xi'an, 710061, China.
Neurochem Int. 2018 Nov;120:238-250. doi: 10.1016/j.neuint.2018.09.005. Epub 2018 Sep 11.
Amyloid β peptide 1-42 (Aβ) could induce cognitive deficits through oxidative stress, inflammation, and neuron death in Alzheimer's disease (AD). MAPK pathways have been thought to mediate Aβ-induced neuroinflammation responses, neuron death and cognitive decline in AD. The α7 nicotinic acetylcholine receptor (α7nAChR) exerts a neuroprotective effect. However, whether α7nAChR alleviates Aβ-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 Aβ degrading enzymes insulin degrading enzyme (IDE) and neprilysin (NEP) were tested using Western blotting. We found that activating α7nAChR or inhibiting p38 or JNK pathway alleviated Aβ-induced cognitive deficits and neuron loss and death by reducing oxidative stress. In addition, activating α7nAChR or inhibiting p38 or JNK pathway also reduced inflammation, which was observed as reduced GFAP and Iba1 levels with different effects on Aβ degrading enzymes. Finally, we found that the activation of α7nAChR led to the downregulation of pp38 and pJNK levels. Conversely, the inhibition of p38 or JNK resulted in the upregulation of α7nAChR levels in the hippocampus and cortex. Our data indicate that the activation of α7nAChR alleviates Aβ-induced neurotoxicity, and this protective effect might act through the downregulation of p38 and JNK MAPKs.
淀粉样β肽 1-42（Aβ）可通过氧化应激、炎症和神经元死亡诱导阿尔茨海默病（AD）中的认知功能障碍。MAPK 途径被认为介导 Aβ 诱导的神经炎症反应、神经元死亡和 AD 中的认知能力下降。α7 烟碱型乙酰胆碱受体（α7nAChR）发挥神经保护作用。然而，α7nAChR 是否通过体内 MAPKs（p38、ERK、JNK）缓解 Aβ 诱导的神经毒性尚不清楚。在我们的研究中，使用 Y 迷宫测试评估 C57BL/6 小鼠的记忆。通过 Nissl 和 Hoechst 染色以及 Western blot 检测 Bax、Bcl-2、Caspase 3 和细胞色素 C 水平评估细胞死亡。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。通过免疫组织化学检测 GFAP 和 Iba1 评估炎症。使用 Western blot 检测 Aβ 降解酶胰岛素降解酶（IDE）和 Neprilysin（NEP）。我们发现，通过减少氧化应激，激活α7nAChR 或抑制 p38 或 JNK 通路可缓解 Aβ 诱导的认知功能障碍和神经元丢失和死亡。此外，激活α7nAChR 或抑制 p38 或 JNK 通路还可减少炎症，这表现为 GFAP 和 Iba1 水平降低，对 Aβ 降解酶的作用不同。最后，我们发现α7nAChR 的激活导致 pp38 和 pJNK 水平下调。相反，p38 或 JNK 的抑制导致海马体和皮质中α7nAChR 水平上调。我们的数据表明，α7nAChR 的激活缓解了 Aβ 诱导的神经毒性，这种保护作用可能通过下调 p38 和 JNK MAPKs 起作用。
