Increased expression of the γ-secretase components presenilin-1 and nicastrin in activated astrocytes and microglia following traumatic brain injury
Increased expression of the γ-secretase components presenilin-1 and nicastrin in activated astrocytes and microglia following traumatic brain injury
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DOI：
10.1002/glia.20638
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发表时间：
2008-04-01
期刊：
影响因子：
6.2
通讯作者：
Stein, Reuven
中科院分区：
文献类型：
--
作者：
Nadler, Yasmine;Alexandrovich, Alexander;Stein, Reuven
γ-分泌酶是一种天冬氨酰蛋白酶，由四种蛋白质组成：早老素（PS）、尼卡斯汀（Net）、APH1和PEN2。这些蛋白质组装成一个膜复合物，在跨膜结构域内切割多种底物。γ-分泌酶切割产物在诸如胚胎发育和阿尔茨海默病（AD）等各种生物学过程中发挥重要作用。γ-分泌酶在脑部病理学中的主要作用与AD以及淀粉样β-肽的产生有关。然而，对于急性脑损伤后γ-分泌酶可能的作用知之甚少。在此，我们通过免疫染色检测了两种γ-分泌酶成分PSI和Net在小鼠三种脑损伤范例中的表达模式：闭合性头部损伤、脑室内注射脂多糖（LPS）以及脑刺伤。我们的结果显示，在未受损和假损伤的大脑中，PS1和Net的表达主要局限于神经元。然而，在损伤后，在非神经元细胞（包括活化的星形胶质细胞和小胶质细胞）中也观察到这两种蛋白质的表达。此外，这些蛋白质在同一星形胶质细胞和小胶质细胞内共表达，这意味着这些细胞在脑损伤后表现出增强的γ-分泌酶活性。鉴于星形胶质细胞和小胶质细胞在脑部疾病中所起的重要作用，我们的研究结果表明，γ-分泌酶可能通过调节星形胶质细胞和小胶质细胞的活化和/或功能参与脑损伤和修复过程。（C）2008威利 - 利斯公司
gamma-Secretase is an aspartyl protease composed of four proteins: presenilin (PS), nicastrin (Net), APH1, and PEN2. These proteins assemble into a membrane complex that cleaves a variety of substrates within the transmembrane domain. The gamma-secretase cleavage products play an important role in various biological processes such as embryonic development and Alzheimer's disease (AD). The major role of gamma-secretase in brain pathology has been linked to AD and to the production of the amyloid P-peptide. However, little is known about the possible role of gamma-secretase following acute brain insult. Here we examined by immunostaining the expression patterns of two gamma-secretase components, PSI and Net, in three paradigms of brain insult in mice: closed head injury, intracerebroventricular injection of LPS, and brain stabbing. Our results show that in naive and sham-injured brains expression of PS1 and Net is restricted mainly to neurons. However, following insult, the expression of both proteins is also observed in nonneuronal cells, consisting of activated astrocytes and microglia. Furthermore, the proteins are coexpressed within the same astrocytes and microglia, implying that these cells exhibit an enhanced gamma-secretase activity following brain damage. In view of the important role played by astrocytes and microglia in brain disorders, our findings suggest that gamma-secretase may participate in brain damage and repair processes by regulating astrocyte and microglia activation and/or function. (C) 2008 Wiley-Liss, Inc.