MicroRNA-144 Is Regulated by Activator Protein-1 (AP-1) and Decreases Expression of Alzheimer Disease-related A Disintegrin and Metalloprotease 10 (ADAM10)
MicroRNA-144 Is Regulated by Activator Protein-1 (AP-1) and Decreases Expression of Alzheimer Disease-related A Disintegrin and Metalloprotease 10 (ADAM10)
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DOI：
10.1074/jbc.m112.381392
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发表时间：
2013-05-10
影响因子：
4.8
通讯作者：
Wang, Zhao
中科院分区：
文献类型：
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作者：
Cheng, Cong;Li, Weiguang;Wang, Zhao
阿尔茨海默病（AD）患者大脑中积累的淀粉样β肽（A β）被认为是该疾病的主要病理生理原因。淀粉样前体蛋白通过α-分泌酶ADAM 10（一种解整合素和金属蛋白酶10）的蛋白水解加工保护大脑免受A β的产生。同时，在AD患者中已经广泛记录了microRNA（miRNAs）的失调或异常表达。在这项研究中，我们证明了miR-144的过表达，这是以前报道的增加在老年灵长类动物的大脑和AD患者，显着降低活性的荧光素酶报告含有ADAM 10的3 '-非翻译区（3'-UTR）和抑制ADAM 10蛋白水平，而miR-144抑制剂导致荧光素酶活性的增加。miR-144的负调控作用严格依赖于其与ADAM 10 3 '-UTR中识别元件的结合。此外，我们还发现激活蛋白-1调节miR-144的转录，并且miR-144的上调至少部分地诱导了A β存在下对ADAM 10蛋白的抑制。此外，我们发现miR-451，一种与miR-144一起从单个基因位点加工的miRNA，也参与了ADAM 10表达的调控。综上所述，我们的数据表明miR-144/451是ADAM 10蛋白的负调节因子，并表明miR-144/451在AD发病机制中的机制作用。
Amyloid beta-peptide (A beta) accumulating in the brain of Alzheimer disease (AD) patients is believed to be the main pathophysiologcal cause of the disease. Proteolytic processing of the amyloid precursor protein by alpha-secretase ADAM10 (a disintegrin and metalloprotease 10) protects the brain from the production of the A beta. Meanwhile, dysregulation or aberrant expression of microRNAs (miRNAs) has been widely documented in AD patients. In this study, we demonstrated that overexpression of miR-144, which was previously reported to be increased in elderly primate brains and AD patients, significantly decreased activity of the luciferase reporter containing the ADAM10 3'-untranslated region (3'-UTR) and suppressed the ADAM10 protein level, whereas the miR-144 inhibitor led to an increase of the luciferase activity. The negative regulation caused by miR-144 was strictly dependent on the binding of the miRNA to its recognition element in the ADAM10 3'-UTR. Moreover, we also showed that activator protein-1 regulates the transcription of miR-144 and the up-regulation of miR-144 at least partially induces the suppression of the ADAM10 protein in the presence of A beta. In addition, we found that miR-451, a miRNA processed from a single gene locus with miR-144, is also involved in the regulation of ADAM10 expression. Taken together, our data therefore demonstrate miR-144/451 is a negative regulator of the ADAM10 protein and suggest a mechanistic role for miR-144/451 in AD pathogenesis.