...
  • 主题
高级搜索  >
历史搜索 清空历史
首页> 外文期刊>FEBS Open Bio >Analysis by a highly sensitive split luciferase assay of the regions involved in APP dimerization and its impact on processing
【24h】

Analysis by a highly sensitive split luciferase assay of the regions involved in APP dimerization and its impact on processing

机译：通过高度敏感的拆分荧光素酶分析法分析涉及APP二聚化的区域及其对加工的影响

获取原文
           
页面导航
  • 摘要
  • 著录项
  • 相似文献
  • 相关主题

摘要

Alzheimer's disease (AD) is a neurodegenerative disease that causes progressive loss of cognitive functions, leading to dementia. Two types of lesions are found in AD brains: neurofibrillary tangles and senile plaques. The latter are composed mainly of the @b-amyloid peptide (A@b) generated by amyloidogenic processing of the amyloid precursor protein (APP). Several studies have suggested that dimerization of APP is closely linked to A@b production. Nevertheless, the mechanisms controlling APP dimerization and their role in APP function are not known. Here we used a new luciferase complementation assay to analyze APP dimerization and unravel the involvement of its three major domains: the ectodomain, the transmembrane domain and the intracellular domain. Our results indicate that within cells full-length APP dimerizes more than its @a and @b C-terminal fragments, confirming the pivotal role of the ectodomain in this process. Dimerization of the APP transmembrane (TM) domain has been reported to regulate processing at the @c-cleavage site. We show that both non-familial and familial AD mutations in the TM GXXXG motifs strongly modulate A@b production, but do not consistently change dimerization of the C-terminal fragments. Finally, we found for the first time that removal of intracellular domain strongly increases APP dimerization. Increased APP dimerization is linked to increased non-amyloidogenic processing.
机译：阿尔茨海默氏病（AD）是一种神经退行性疾病，会引起认知功能的逐步丧失，从而导致痴呆。在AD脑中发现两种类型的病变：神经原纤维缠结和老年斑。后者主要由淀粉样前体蛋白（APP）的淀粉样生成过程产生的β-淀粉样肽（A @ b）组成。多项研究表明，APP的二聚化与A @ b的产生密切相关。然而，控制APP二聚化的机制及其在APP功能中的作用尚不清楚。在这里，我们使用了一种新型的荧光素酶互补测定法来分析APP二聚化并阐明其三个主要结构域的参与：胞外结构域，跨膜结构域和细胞内结构域。我们的结果表明，在细胞内，全长APP的二聚体比其@a和@b C末端片段更多，这证实了胞外域在此过程中的关键作用。据报道，APP跨膜（TM）结构域的二聚化可调节@ c-切割位点处的加工。我们显示，TM GXXXG图案中的非家族性和家族性AD突变都强烈调节A @ b的产生，但不能始终如一地改变C末端片段的二聚化。最后，我们首次发现细胞内结构域的去除强烈地增强了APP二聚化。 APP二聚化的增加与非淀粉样生成过程的增加有关。

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