Division of Brain Diseases, Center for Biomedical Sciences, National Institute of Health, Seoul, Korea.
J Neurosci Res. 2010 Jul;88(9):1926-33. doi: 10.1002/jnr.22356.
The presenilin/gamma-secretase protease cleaves many type-I membrane proteins, including the amyloid beta-protein (Abeta) precursor (APP). Previous studies have shown that apoptosis induces alterations in Abeta production in a caspase-dependent manner. Here, we report that staurosporine (STS)-induced apoptosis induces caspase-8 and/or-2-dependent gamma-secretase activation. Blocking of caspase activity with caspase-8 inhibitor z-IETD-fmk, and caspase-2 inhibitor z-VDVAD-fmk reduced Abeta production by STS in H4 cells expressing the Swedish mutant of APP (HSW) or APP-C99 (H4-C99). There was no inhibitory effect of other caspases (-1, -3, -5, -6, -9) on Abeta production by STS. This finding was further supported by evidence that siRNA transfection, depleting caspase-2 or -8 levels, lowered Abeta production in HSW and H4-C99 cells without affecting expression of APP or gamma-secretase complex. In addition, Abeta production by STS was decreased by JNK inhibitors, SP600125. These results suggest that caspase-2 and/or -8 is involved in presenilin/gamma-secretase activation and Abeta production in apoptosis.
早老素/γ-分泌酶蛋白酶切割许多 I 型膜蛋白，包括淀粉样β蛋白（Aβ）前体（APP）。先前的研究表明，细胞凋亡以胱天蛋白酶依赖性方式诱导 Aβ产生的改变。在这里，我们报告说，星形孢菌素（STS）诱导的细胞凋亡诱导胱天蛋白酶-8 和/或-2 依赖性 γ-分泌酶激活。用胱天蛋白酶-8 抑制剂 z-IETD-fmk 和胱天蛋白酶-2 抑制剂 z-VDVAD-fmk 阻断胱天蛋白酶活性，可减少表达瑞典突变 APP（HSW）或 APP-C99（H4-C99）的 H4 细胞中 STS 诱导的 Aβ产生。STS 诱导的 Aβ产生对其他胱天蛋白酶（-1、-3、-5、-6、-9）没有抑制作用。siRNA 转染、降低胱天蛋白酶-2 或-8 水平的证据进一步支持了这一发现，降低了 HSW 和 H4-C99 细胞中 Aβ的产生，而不影响 APP 或 γ-分泌酶复合物的表达。此外，STS 诱导的 Aβ产生被 JNK 抑制剂 SP600125 减少。这些结果表明，胱天蛋白酶-2 和/或-8 参与细胞凋亡中的早老素/γ-分泌酶激活和 Aβ产生。
