...
  • 主题
高级搜索  >
历史搜索 清空历史
首页> 外文期刊>The journals of gerontology.Series A. Biological sciences and medical sciences >Sildenafil Decreases BACE1 and Cathepsin B Levels and Reduces APP Amyloidogenic Processing in the SAMP8 Mouse
【24h】

Sildenafil Decreases BACE1 and Cathepsin B Levels and Reduces APP Amyloidogenic Processing in the SAMP8 Mouse

机译：西地那非可降低BACE1和组织蛋白酶B的水平，并减少SAMP8小鼠APP淀粉样蛋白生成过程。

获取原文
获取原文并翻译 | 示例
           
页面导航
  • 摘要
  • 著录项
  • 相似文献
  • 相关主题

摘要

The senescence-accelerated mouse-prone 8 (SAMP8), used as a model of aging, displays many established pathological features of Alzheimer's disease. Cognitive impairments and increased levels of hyperphosphorylated tau are found in the hippocampus of SAMP8 mice along with an increased beta-secretase activity and amyloid-beta (A beta) depositions that increase in number and extent with age. Based on a previous study from our laboratory showing an amelioration of cognitive impairments and tau pathology by sildenafil, in this study we tested whether this drug could also modulate the amyloid precursor protein amyloidogenic processing in this mouse model. Our results show that the protein levels of the beta-secretases beta-site amyloid precursor protein cleaving enzyme 1 and cathepsin B are higher in the hippocampus of 9-month-old SAMP8 mice than those of age-matched senescence-resistant-1. Sildenafil (7.5 mg/kg for 4 weeks) attenuated learning and memory impairments shown by SAMP8 mice in the passive avoidance test. The increased expression of beta-site amyloid precursor protein cleaving enzyme 1 was also reduced by sildenafil, an effect paralleled to decreases in the activities of two beta-site amyloid precursor protein cleaving enzyme 1 modulators, calpain and cyclin-dependent kinase 5 protein. Interestingly, sildenafil enhanced both Akt and glycogen synthase kinase-3 beta (ser9) phosphorylation, which could be mediating the reduction in cathepsin B levels found in the hippocampus of sildenafil-treated SAMP8 mice. Sildenafil-induced reduction in beta-site amyloid precursor protein cleaving enzyme 1 and cathepsin B expression in SAMP8 mice was associated with a decrease in hippocampal A beta(42) levels which, in turn, could mediate the parallel decline in glial fibrillary acidic protein expression observed in these animals. These findings highlight the therapeutic potential of sildenafil in Alzheimer's disease pathogenesis.
机译：衰老加速的易小鼠衰老8（SAMP8）用作衰老模型，显示出许多已建立的阿尔茨海默氏病病理特征。在SAMP8小鼠的海马中发现认知障碍和高磷酸化tau蛋白水平升高，同时随着年龄的增长，β-分泌酶活性和淀粉样-β（A beta）沉积物增加。根据来自我们实验室的先前研究显示西地那非改善了认知障碍和tau病理，在这项研究中，我们测试了该药物是否还可以调节该小鼠模型中的淀粉样前体蛋白淀粉样生成过程。我们的结果表明，在9个月大的SAMP8小鼠的海马中，β-分泌酶β-位淀粉样蛋白前体蛋白裂解酶1和组织蛋白酶B的蛋白质水平高于年龄相匹配的抗衰老-1小鼠。西地那非（7.5 mg / kg，持续4周）可减轻SAMP8小鼠在被动回避测试中显示的学习和记忆障碍。西地那非也降低了β-位淀粉样蛋白前体蛋白裂解酶1的表达增加，这种作用与两种β-位淀粉样蛋白前体蛋白裂解酶1调节剂，钙蛋白酶和细胞周期蛋白依赖性激酶5蛋白的活性降低平行。有趣的是，西地那非增强了Akt和糖原合酶激酶3β（ser9）的磷酸化，这可能介导了西地那非治疗的SAMP8小鼠海马中组织蛋白酶B水平的降低。 Sildenafil诱导SAMP8小鼠的β-位淀粉样蛋白前体蛋白裂解酶1和组织蛋白酶B表达降低与海马A beta（42）水平降低有关，而后者又可能介导神经胶质纤维酸性蛋白表达的平行下降在这些动物中观察到。这些发现突出了西地那非在阿尔茨海默氏病发病机理中的治疗潜力。

著录项

相似文献

  • 外文文献
  • 中文文献
  • 专利
获取原文

客服邮箱：kefu@zhangqiaokeyan.com

京公网安备：11010802029741号 ICP备案号：京ICP备15016152号-6 六维联合信息科技 (北京) 有限公司©版权所有

  • 客服微信

  • 服务号