TNFAIP1 Mediates Formaldehyde-Induced Neurotoxicity by Inhibiting the Akt/CREB Pathway in N2a Cells
TNFAIP1 Mediates Formaldehyde-Induced Neurotoxicity by Inhibiting the Akt/CREB Pathway in N2a Cells
复制标题
TNFAIP1 通过抑制 N2a 细胞中的 Akt/CREB 通路介导甲醛诱导的神经毒性
DOI：
10.1007/s12640-020-00199-9
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发表时间：
2020-04-25
影响因子：
3.7
通讯作者：
Xiang, Shuanglin
中科院分区：
文献类型：
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作者：
Yi, Junzhi;Zhu, Min;Xiang, Shuanglin
甲醛是一种常见的空气污染物。暴露于外源性FA可引起神经系统损伤，如学习和记忆障碍、平衡功能障碍和睡眠障碍。内源性FA的过量产生也会导致记忆障碍，并被认为与阿尔茨海默病（AD）有关。肿瘤坏死因子α诱导蛋白1 （TNFAIP1）在神经发育和神经系统疾病中起着至关重要的作用。然而，TNFAIP1在fa诱导的神经毒性中的作用尚不清楚。本研究利用小鼠神经母细胞瘤细胞系（N2a细胞），探讨了TNFAIP1在FA诱导的神经毒性中的作用机制，Akt/CREB信号通路的参与，以及TNFAIP1的表达如何受到FA的调节。我们发现，暴露于100 μM或200 μM FA 24 h可导致细胞活力降低，细胞凋亡和神经突缩回增加，活性氧（ROS）水平升高，TNFAIP1蛋白表达上调，Akt/CREB通路中磷酸化Akt和CREB水平降低。使用TNFAIP1小干扰RNA （siRNA）表达载体敲低TNFAIP1可阻止FA抑制Akt/CREB通路，从而减少细胞凋亡，恢复细胞活力和神经突生长。维生素E （Vit E）清除ROS可抑制fa介导的TNFAIP1表达上调。这些结果表明，FA通过诱导氧化应激增加TNFAIP1的表达，而上调的TNFAIP1随后抑制Akt/CREB通路，从而导致细胞凋亡和神经突收缩。因此，TNFAIP1是减轻fa诱导的神经毒性和相关神经系统疾病的潜在靶点。
Formaldehyde (FA) is a common air pollutant. Exposure to exogenous FA can cause damage to the nervous system, such as learning and memory impairment, balance dysfunction, and sleep disorders. Excessive production of endogenous FA also causes memory impairment and is thought to be associated with Alzheimer’s disease (AD). Tumor necrosis factor alpha-induced protein 1 (TNFAIP1) plays a crucial role in neurodevelopment and neurological diseases. However, the role of TNFAIP1 in FA-induced neurotoxicity is unclear. Herein, using a mouse neuroblastoma cell line (N2a cells), we explored the mechanism of TNFAIP1 in FA-induced neurotoxicity, the involvement of the Akt/CREB signaling pathway, and how the expression of TNFAIP1 is regulated by FA. We found that exposure to 100 μM or 200 μM FA for 24 h led to decreased cell viability, increased cell apoptosis and neurite retraction, increased reactive oxygen species (ROS) levels, upregulated protein expression of TNFAIP1 and decreased the levels of phosphorylated Akt and CREB in the Akt/CREB pathway. Knockdown of TNFAIP1 using a TNFAIP1 small interfering RNA (siRNA) expression vector prevented FA from inhibiting the Akt/CREB pathway, thus reducing cell apoptosis and restoring cell viability and neurite outgrowth. Clearance of ROS by vitamin E (Vit E) repressed the FA-mediated upregulation of TNFAIP1 expression. These results suggest that FA increases the expression of TNFAIP1 by inducing oxidative stress and that upregulated TNFAIP1 then inhibits the Akt/CREB pathway, consequently leading to cell apoptosis and neurite retraction. Therefore, TNFAIP1 is a potential target for alleviating FA-induced neurotoxicity and related neurological disorders.