State Key Laboratory of Developmental Biology of Freshwater Fish, School of Life Sciences, Hunan Normal University, Changsha, 410081, Hunan, China.
Key Laboratory of Tissue Engineering and Regenerative Medicine of Zhejiang Province, School of Medicine, Zhejiang University, Hangzhou, China.
Neurotox Res. 2020 Jun;38(1):184-198. doi: 10.1007/s12640-020-00199-9. Epub 2020 Apr 25.
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.
甲醛（FA）是一种常见的空气污染物。接触外源性 FA 可导致神经系统损伤，如学习和记忆障碍、平衡功能障碍和睡眠障碍。内源性 FA 过量产生也会导致记忆障碍，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）在神经发育和神经疾病中发挥着关键作用。然而，TNFAIP1 在 FA 诱导的神经毒性中的作用尚不清楚。在此，我们使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 信号通路的参与情况，以及 FA 如何调节 TNFAIP1 的表达。我们发现，暴露于 100 μM 或 200 μM FA 24 h 会导致细胞活力降低、细胞凋亡和神经突回缩增加、活性氧（ROS）水平升高、TNFAIP1 蛋白表达上调以及 Akt/CREB 通路中磷酸化 Akt 和 CREB 水平降低。使用 TNFAIP1 小干扰 RNA（siRNA）表达载体下调 TNFAIP1 可防止 FA 抑制 Akt/CREB 通路，从而减少细胞凋亡并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 抑制 Akt/CREB 通路，导致细胞凋亡和神经突回缩。因此，TNFAIP1 是缓解 FA 诱导的神经毒性和相关神经疾病的潜在靶点。
