Department of Molecular Biology & Immunology, University of North Texas Health Science Center at Fort Worth, 3500 Camp Bowie Boulevard, Fort Worth, TX 76123, USA.
Brain Res. 2012 Apr 11;1448:117-28. doi: 10.1016/j.brainres.2012.01.066. Epub 2012 Feb 3.
Presenilin-1 (PS1) is a multifunctional protein involved in many cellular functions including the processing of type 1 membrane proteins such as β-amyloid precursor protein (APP) and Notch 1 receptor. PS1 acts as the catalytic subunit of the γ-secretase complex, and participates in Notch 1 processing to release Notch intracellular domain (NICD) in the cytoplasm. NICD subsequently migrates to the nucleus and causes Notch signaling by increasing the expression of the Hes1 gene. We have previously shown that inhibition of basal activity of c-jun-NH2-terminal kinase (JNK) with JNK-specific inhibitor SP600125 represses the expression of PS1 and γ-secretase activity by increasing p53 level in SK-N-SH cell line in vitro (Lee and Das, 2008, 2010). However, it is largely unknown whether PS1 can be effectively suppressed in vivo in adult mouse brains. In this report we showed that intraperitoneal (i.p) injection of JNK-specific inhibitor SP600125 decreased p-JNK level, and reduced PS1 expression by increasing p53 level in adult mouse brains. We also showed that suppression of PS1 expression by SP600125 reduced γ-secretase activity which decreased Notch 1 processing to reduce NICD in mouse brains. Furthermore, inhibition of Notch 1 processing by SP600125 decreased Notch 1 signaling by reducing the expression of the NICD target Hes1 gene in mouse brains without induction of apoptosis. These results provide insights for further study on PS1-mediated reduction of Notch 1 and APP processing for the treatment of Alzheimer's disease.
早老素 1（PS1）是一种多功能蛋白，参与许多细胞功能，包括 1 型膜蛋白如β-淀粉样前体蛋白（APP）和 Notch1 受体的加工。PS1 作为 γ-分泌酶复合物的催化亚基，参与 Notch1 加工，将 Notch 细胞内结构域（NICD）释放到细胞质中。NICD 随后迁移到细胞核，通过增加 Hes1 基因的表达来引起 Notch 信号转导。我们之前已经表明，使用 JNK 特异性抑制剂 SP600125 抑制 c-jun-NH2-末端激酶（JNK）的基础活性可通过增加 SK-N-SH 细胞系中 p53 水平来抑制 PS1 的表达和 γ-分泌酶活性（Lee 和 Das，2008 年，2010 年）。然而，在成年小鼠大脑中体内是否可以有效地抑制 PS1 尚不清楚。在本报告中，我们表明，腹腔内（i.p）注射 JNK 特异性抑制剂 SP600125 可降低 p-JNK 水平，并通过增加 p53 水平来降低成年小鼠大脑中的 PS1 表达。我们还表明，SP600125 抑制 PS1 表达可降低 γ-分泌酶活性，从而减少 Notch1 加工以减少小鼠大脑中的 NICD。此外，SP600125 抑制 Notch1 加工可减少 Notch1 信号转导，从而减少 NICD 靶基因 Hes1 基因在小鼠大脑中的表达，而不会诱导细胞凋亡。这些结果为进一步研究 PS1 介导的 Notch1 和 APP 加工减少用于治疗阿尔茨海默病提供了思路。
