FDA-preapproved drugs targeted to the translational regulation and processing of the amyloid precursor protein
FDA-preapproved drugs targeted to the translational regulation and processing of the amyloid precursor protein
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DOI：
10.1385/jmn:24:1:129
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发表时间：
2004-01-01
影响因子：
3.1
通讯作者：
Rogers, JT
中科院分区：
文献类型：
--
作者：
Morse, LJ;Payton, SM;Rogers, JT
编码阿尔茨海默氏症淀粉样前体蛋白（APP）的转录本的5'非翻译区（5' UTR）是决定脑源性细胞中存在的细胞内APP全蛋白量的关键调节序列。使用神经母细胞瘤细胞（SY 5 Y），我们开发了基于转染的FDA药物文库筛选，以鉴定限制从APP 5 'UTR翻译的APP荧光素酶报告基因表达的化合物。帕罗西汀（Paxil（TM））、二巯基丙醇、苯丝氨酸、去铁胺、四硫羟甲基丙酸和阿奇霉素是随后发现也抑制APP全蛋白水平或改变APP裂解（阿奇霉素）的六种先导物。由于在许多系统中APP全蛋白水平与Abeta肽输出成比例，我们测试了帕罗西汀和二巯基丙醇限制Abeta分泌的功效，如通过ELISA测定所测量的。帕罗西汀和二巯基丙醇限制透镜上皮细胞（B3细胞）的A β肽分泌。有趣的是，帕罗西汀改变了转铁蛋白受体mRNA的稳态水平。这些数据表明，这种5-羟色胺再摄取抑制剂（SSRI）提供了额外的药理作用，螯合细胞内铁或改变细胞内铁的分布。预测改变的铁分布将间接限制APP全蛋白表达和Abeta肽分泌。
The 5' untranslated region (5'UTR) of the transcript encoding the Alzheimer's amyloid precursor protein (APP) is a key regulatory sequence that determines the amount of intracellular APP holoprotein present in brain derived cells. Using neuroblastoma cells (SY5Y) we developed a transfection based screen of a library of FDA drugs to identify compounds that limited APP luciferase reporter expression translated from the APP 5'UTR. Paroxetine (Paxil(TM)), dimercaptopropanol, phenserine, desferrioxamine, tetrathiolmobdylate, and azithromycin were six leads that were subsequently found to also suppress APP holoprotein levels or to alter APP cleavage (azithromycin). Since APP holoprotein levels are proportionate to Abeta peptide output in many systems we tested the efficacy of paroxetine and dimercaptopropanol to limit Abeta secretion as measured by ELISA assays. Paroxetine and dimercaptopropanol limited Abeta peptide secretion from lens epithelial cells (B3 cells). Interestingly, paroxetine changed the steady-state levels of transferrin receptor mRNAs. These data suggested that this serotonin reuptake inhibitor (SSRI) provided extra pharmacological action to chelate interacellular iron or change the intracellular iron distribution. An altered iron distribution would be predicted to indirectly limit APP holoprotein expression and Abeta peptide secretion.