MKP-1 reduces Aβ generation and alleviates cognitive impairments in Alzheimer's disease models
MKP-1 reduces Aβ generation and alleviates cognitive impairments in Alzheimer's disease models
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MKP-1 可减少阿尔茨海默病模型中 Abeta 的生成并减轻认知障碍。
DOI：
10.1038/s41392-019-0091-4
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发表时间：
2019-12-06
影响因子：
39.3
通讯作者：
Dong, Zhifang
中科院分区：
文献类型：
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作者：
Du, Yehong;Du, Yexiang;Dong, Zhifang
丝裂原活化蛋白激酶（MAPK）磷酸酶1（MKP-1）是MAPK的一种重要的负性调节因子，通过使MAPKs的酪氨酸和苏氨酸残基去磷酸化。MAPK信号通路的失调与阿尔茨海默病（AD）有关。然而，MKP-1在AD发病机制中的作用仍然难以捉摸。在这里，我们报告AD患者和AD小鼠模型的脑组织中MKP-1水平降低。MKP-1基因表达的减少似乎是通过MKP-1基因启动子中的转录因子特异性蛋白1（Sp1）顺式作用结合元件进行转录抑制的结果。β淀粉样蛋白（A β）诱导的Sp1激活降低MKP-1表达。然而，MKP-1的上调通过使细胞外信号调节激酶1/2（ERK）/MAPK信号通路失活而抑制A β前体蛋白（APP）和β位点APP裂解酶1的表达。此外，MKP-1的上调减少了APP/PS1转基因小鼠的A β产生和斑块形成，并改善了海马长时程增强（LTP）和认知缺陷。我们的研究结果表明，MKP-1损伤促进AD的发病机制，而MKP-1的上调起着神经保护作用，以减少阿尔茨海默病相关的表型。因此，这项研究表明，MKP-1是一种新的分子治疗AD。
Mitogen-activated protein kinase (MAPK) phosphatase 1 (MKP-1) is an essential negative regulator of MAPKs by dephosphorylating MAPKs at both tyrosine and threonine residues. Dysregulation of the MAPK signaling pathway has been associated with Alzheimer's disease (AD). However, the role of MKP-1 in AD pathogenesis remains elusive. Here, we report that MKP-1 levels were decreased in the brain tissues of patients with AD and an AD mouse model. The reduction in MKP-1 gene expression appeared to be a result of transcriptional inhibition via transcription factor specificity protein 1 (Sp1) cis-acting binding elements in the MKP-1 gene promoter. Amyloid-beta (A beta)-induced Sp1 activation decreased MKP-1 expression. However, upregulation of MKP-1 inhibited the expression of both A beta precursor protein (APP) and beta-site APP-cleaving enzyme 1 by inactivating the extracellular signal-regulated kinase 1/2 (ERK)/MAPK signaling pathway. Furthermore, upregulation of MKP-1 reduced A beta production and plaque formation and improved hippocampal long-term potentiation (LTP) and cognitive deficits in APP/PS1 transgenic mice. Our results demonstrate that MKP-1 impairment facilitates the pathogenesis of AD, whereas upregulation of MKP-1 plays a neuroprotective role to reduce Alzheimer-related phenotypes. Thus, this study suggests that MKP-1 is a novel molecule for AD treatment.