Xiao Ye, Li Yadan, Zhang Huihui, Yang Liping, Jiang Yinghua, Wei Chenxi, Feng Xing, Xun Yu, Yuan Shishan, Xiang Shuanglin, Liu Ning
Key Laboratory of Study and Discovery of Small Targeted Molecules of Hunan Province, School of Medicine, Hunan Normal University, Changsha, 410081, Hunan, China.
State Key Laboratory of Developmental Biology of Freshwater Fish, School of Life Sciences, The National & Local Joint Engineering Laboratory of Animal Peptide Drug Development, School of Life Sciences, Hunan Normal University, Changsha, 410081, Hunan, China.
J Mol Neurosci. 2021 Jun;71(6):1221-1233. doi: 10.1007/s12031-020-01748-9. Epub 2020 Nov 7.
Alzheimer's disease (AD) poses a significant threat to human life and health. The intraneuronal accumulation of β-amyloid (Aβ) plaques in the brains of AD patients results in neuronal cell death, which is a key factor that triggers multiple changes in the pathogenesis of AD. The inhibition of Aβ-induced neuronal cell death may potentially help in the intervention and treatment of AD. Our previous study reported that tumor necrosis factor α-induced protein 1 (TNFAIP1) is induced by and promotes Aβ-induced neurotoxicity in mouse neuronal cells, but the roles and regulatory mechanisms of TNFAIP1 are still largely unknown. In this study, our experimental results show that TNFAIP1 and p-TNFAIP1 (phosphorylation of TNFAIP1 at Ser280) are overexpressed in the neurons of the cortex and hippocampus in the brains of APP/PS1 mice, and the transcription factor NF-κB is involved in the Aβ-induced upregulation of TNFAIP1. Moreover, our results suggest that TNFAIP1 contributes to the Aβ-induced reactive oxygen species (ROS) production, decreased mitochondrial membrane potential (∆Ψm), and neuronal cell death in human SH-SY5Y cells. We further revealed that Aβ increases the binding of TNFAIP1 to RhoB, and knockdown of RhoB attenuates the TNFAIP1-induced apoptosis of human SH-SY5Y cells. These data suggest that TNFAIP1 is closely associated with AD pathogenesis, and overexpression of TNFAIP1 in the neurons of the brains of AD patients plays a role in apoptosis, at least in part, via RhoB signaling.
阿尔茨海默病（AD）对人类生命和健康构成重大威胁。AD患者大脑中β-淀粉样蛋白（Aβ）斑块在神经元内的积累导致神经元细胞死亡，这是引发AD发病机制中多种变化的关键因素。抑制Aβ诱导的神经元细胞死亡可能有助于AD的干预和治疗。我们之前的研究报道，肿瘤坏死因子α诱导蛋白1（TNFAIP1）由Aβ诱导产生并促进其在小鼠神经元细胞中的神经毒性作用，但TNFAIP1的作用和调控机制仍大多未知。在本研究中，我们的实验结果表明，TNFAIP1和p-TNFAIP1（TNFAIP1在Ser280位点的磷酸化形式）在APP/PS1小鼠大脑皮层和海马神经元中过表达，并且转录因子NF-κB参与了Aβ诱导的TNFAIP1上调。此外，我们的结果表明，TNFAIP1在人SH-SY5Y细胞中促使Aβ诱导活性氧（ROS）生成、线粒体膜电位（∆Ψm）降低以及神经元细胞死亡。我们进一步揭示，Aβ增加了TNFAIP1与RhoB的结合，敲低RhoB可减弱TNFAIP1诱导的人SH-SY5Y细胞凋亡。这些数据表明，TNFAIP1与AD发病机制密切相关，AD患者大脑神经元中TNFAIP1的过表达至少部分通过RhoB信号通路在细胞凋亡中发挥作用。
