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首页> 外文期刊>Neuron >Transcriptional regulation of beta-secretase by p25/cdk5 leads to enhanced amyloidogenic processing.
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Transcriptional regulation of beta-secretase by p25/cdk5 leads to enhanced amyloidogenic processing.

机译：p25 / cdk5对β-分泌酶的转录调控导致淀粉样蛋白生成过程增强。

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摘要

Cyclin-dependent kinase 5 (cdk5) has been implicated in Alzheimer's disease (AD) pathogenesis. Here, we demonstrate that overexpression of p25, an activator of cdk5, led to increased levels of BACE1 mRNA and protein in vitro and in vivo. A p25/cdk5 responsive region containing multiple sites for signal transducer and activator of transcription (STAT1/3) was identified in the BACE1 promoter. STAT3 interacts with the BACE1 promoter, and p25-overexpressing mice had elevated levels of pSTAT3 and BACE1, whereas cdk5-deficient mice had reduced levels. Furthermore, mice with a targeted mutation in the STAT3 cdk5 responsive site had lower levels of BACE1. Increased BACE levels in p25 overexpressing mice correlated with enhanced amyloidogenic processing that could be reversed by a cdk5 inhibitor. These data demonstrate a pathway by which p25/cdk5 increases the amyloidogenic processing of APP through STAT3-mediated transcriptional control of BACE1 that could have implications for AD pathogenesis.
机译：细胞周期蛋白依赖性激酶5（cdk5）已被证明与阿尔茨海默氏病（AD）发病机理有关。在这里，我们证明了cdk5激活剂p25的过表达导致体内外BACE1 mRNA和蛋白质水平升高。在BACE1启动子中鉴定出一个p25 / cdk5响应区，该区包含多个位点，用于信号转导和转录激活（STAT1 / 3）。 STAT3与BACE1启动子相互作用，p25过表达的小鼠的pSTAT3和BACE1水平升高，而cdk5缺陷的小鼠水平降低。此外，在STAT3 cdk5反应位点具有目标突变的小鼠的BACE1水平较低。在p25过表达的小鼠中，BACE水平升高与淀粉样蛋白生成过程增强有关，而cdk5抑制剂可以逆转这种过程。这些数据证明了p25 / cdk5通过STAT3介导的BACE1转录控制增加APP的淀粉样蛋白加工过程的途径，这可能对AD发病机制有影响。

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