Mitogen-activated protein kinase phosphatase 1 protects PC12 cells from amyloid beta-induced neurotoxicity

作者：Gu, Yue; Ma, Lian-Jun; Bai, Xiao-Xue; Jie, Jing; Zhang, Xiu-Fang; Chen, Dong; Li, Xiao-Ping^*

来源：Neural Regeneration Research, 2018, 13(10): 1842-1850.

DOI：10.4103/1673-5374.238621

• nerve regeneration
• mitogen-activated protein kinase phosphatase 1
• c-Jun N-terminal kinase signaling pathway
• Alzheimer's disease
• neurons
• dementia
• apoptosis
• RNA interference
• lentivirus
• inflammation
• oxidative stress
• neural regeneration

The mitogen-activated protein kinase (MAPK) signaling pathway plays an important role in the regulation of cell growth, proliferation, differentiation, transformation and death. Mitogen-activated protein kinase phosphatase 1 (MKP1) has an inhibitory effect on the p38MAPK and JNK pathways, but it is unknown whether it plays a role in A beta-induced oxidative stress and neuronal inflammation. In this study, PC12 cells were infected with MKP1 shRNA, MKP1 lentivirus or control lentivirus for 12 hours, and then treated with 0.1, 1, 10 or 100 mu M amyloid beta 42 (A beta(42)). The cell survival rate was measured using the cell counting kit-8 assay. MKP1, tumor necrosis factor-alpha (TNF-alpha) and interleukin-1 beta (IL-1 beta) mRNA expression levels were analyzed using quantitative real time-polymerase chain reaction. MKP1 and phospho-c-Jun N-terminal kinase (JNK) expression levels were assessed using western blot assay. Reactive oxygen species (ROS) levels were detected using 2',7'-dichlorofluorescein diacetate. Mitochondria) membrane potential was measured using flow cytometry. Superoxide dismutase activity and malondialdehyde levels were evaluated using the colorimetric method. Lactate dchydrogenase activity was measured using a microplate reader. Caspase-3 expression levels were assessed by enzyme-linked immunosorbent assay. Apoptosis was evaluated using the terminal dcoxynucicotidyl transferase dUTP nick end labeling method. MKP1 overexpression inhibited A beta-induced JNK phosphorylation and the increase in ROS levels. It also suppressed the A beta-induced increase in TNF-alpha and IL-1 beta levels as well as apoptosis in PC12 cells. In contrast, MKP1 knockdown by RNA interference aggravated A beta-induced oxidative stress, inflammation and cell damage in PC12 cells. Furthermore, the JNK-specific inhibitor SP600125 abolished this effect of MKP1 knockdown on A beta-induced neurotoxicity. Collectively, these results show that MKP1 mitigates A beta-induced apoptosis, oxidative stress and neuroinflammation by inhibiting the JNK signaling pathway, thereby playing a neuroprotectivc role.

• 出版日期2018-10
• 单位吉林大学