MLK3‐MKK3/6‐P38MAPK cascades following N‐methyl‐D‐aspartate receptor activation contributes to amyloid‐β peptide‐induced apoptosis in SH‐SY5Y cells
MLK3‐MKK3/6‐P38MAPK cascades following N‐methyl‐D‐aspartate receptor activation contributes to amyloid‐β peptide‐induced apoptosis in SH‐SY5Y cells
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DOI：
10.1002/jnr.23354
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发表时间：
2014-06
影响因子：
4.2
通讯作者：
Fang Zhou;Yan Xu;X. Hou
中科院分区：
文献类型：
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作者：
Fang Zhou;Yan Xu;X. Hou
淀粉样β肽（Aβ）与阿尔茨海默病（AD）的发生发展有关，但其潜在的分子机制尚不清楚。本研究探讨了N-甲基-D-天冬氨酸（NMDA）受体在Aβ神经毒性中诱发的促凋亡信号。寡聚体Aβ25-35孵育导致神经元SH‐ SY 5 Y细胞显著凋亡。预先给予有效的NMDA受体拮抗剂MK 801可促进神经元存活。NVP-AAM 077和Ro 25 -6981（分别为GluN 2A-和GluN 2B-亚基选择性NMDA受体拮抗剂）均显示出与MK 801相似的作用，支持含GluN 2A-或GluN 2B-的NMDA受体在Aβ神经毒性中的关键作用。暴露于寡聚体Aβ25-35可增加SH-SY 5 Y细胞中混合谱系激酶3（MLK 3）、双特异性丝裂原活化蛋白激酶激酶3/6（MKK 3/6）和P38丝裂原活化蛋白激酶（P38 MAPK）的磷酸化（活化）。SB 239063抑制P38 MAPK的活化具有神经保护作用。K252 a减弱了MLK 3、MKK 3/6和P38 MAPK的磷酸化，但也部分阻止了SH-SY 5 Y细胞凋亡。MK 801、NVP-AAM 077和Ro 25 -6981消除了由寡聚Aβ25-35诱导的MLK 3-MKK 3/6-P38 MAPK活化。这些结果表明，含有GluN 2A-或GluN 2B-的NMDA受体的激活负责MLK 3-MKK 3/6-P38 MAPK级联反应的激活，这有助于Aβ介导的细胞凋亡。© 2014 Wiley Periodicals，Inc.
Amyloid‐β peptide (Aβ) has been implicated in the development of Alzheimer's disease (AD), but the underlying molecular mechanisms remain unclear. The present study explores the proapoptosis signaling evoked by N‐methyl‐D‐aspartate (NMDA) receptors in Aβ neurotoxicity. Oligomeric Aβ25–35 incubation resulted in significant apoptosis of neuronal SH‐SY5Y cells. Preadministration of the potent NMDA receptor antagonist MK801 promoted neuronal survival. Both NVP‐AAM077 and Ro25–6981, GluN2A‐ and GluN2B‐subunit‐selective NMDA receptor antagonists, respectively, showed effects similar to those of MK801, supporting a critical role of GluN2A‐ or GluN2B‐containing NMDA receptors in Aβ neurotoxicity. Exposure to oligomeric Aβ25–35 increased the phosphorylation (activation) of mixed‐lineage kinase 3 (MLK3), dual‐specific mitogen‐activated protein kinase kinase 3/6 (MKK3/6), and P38 mitogen‐activated protein kinase (P38MAPK) in SH‐SY5Y cells. Inhibition of P38MAPK activation by SB239063 had a neuroprotective effect. K252a attenuated the phosphorylation of MLK3, MKK3/6, and P38MAPK but also partially prevented SH‐SY5Y cells apoptosis. MK801, NVP‐AAM077, and Ro25–6981, abrogated the MLK3‐MKK3/6‐P38MAPK activation induced by oligomeric Aβ25–35. These results suggest that the activation of GluN2A‐ or GluN2B‐containing NMDA receptors is responsible for the activation of MLK3‐MKK3/6‐P38MAPK cascades, which contributes to Aβ‐mediated cell apoptosis. © 2014 Wiley Periodicals, Inc.