College of Pharmacy, Sungkyunkwan University, 300 Cheoncheon-dong, Jangan-gu, Suwon 440-746, Republic of Korea.
Neurosci Lett. 2010 Jan 29;469(3):425-8. doi: 10.1016/j.neulet.2009.12.043. Epub 2009 Dec 23.
Presenilins are the catalytic subunit of the large gamma-secretase complex, that promotes intramembranous proteolysis of the beta-amyloid precursor protein (APP), resulting in the production of beta-amyloid (A beta). Mutant presenilin causes early-onset familial Alzheimer's disease (FAD), is related to abnormal Ca(2+) signaling, and render cells vulnerable to cell death. In the present study, we demonstrated that Ca(2+)-mediated cell death is functionally associated with gamma-secretase activity. We found that gamma-secretase activity was elevated during Ca(2+)-mediated cell death. Using selective gamma-secretase inhibitors, we examined the role of gamma-secretase in cell death triggered by increased intracellular Ca(2+). Indeed, treatment with the selective gamma-secretase inhibitors, compound E, DAPT, or L-685.458 significantly decreased Ca(2+)-triggered cell death with that of the controls, but did not affect staurosporin or tunicamycin-mediated cell death. These results implicate the role of gamma-secretase activity in Ca(2+)-mediated cell death.
早老素是大型 γ-分泌酶复合物的催化亚基，促进β淀粉样前体蛋白（APP）的跨膜蛋白水解，导致β-淀粉样肽（Aβ）的产生。突变早老素导致早发性家族性阿尔茨海默病（FAD），与异常的 Ca（2+）信号有关，并使细胞易发生细胞死亡。在本研究中，我们证明了 Ca（2+）介导的细胞死亡与 γ-分泌酶活性在功能上相关。我们发现，在 Ca（2+）介导的细胞死亡过程中，γ-分泌酶活性升高。使用选择性 γ-分泌酶抑制剂，我们研究了 γ-分泌酶在由细胞内 Ca（2+）增加引发的细胞死亡中的作用。事实上，用选择性 γ-分泌酶抑制剂化合物 E、DAPT 或 L-685.458 处理可显著降低 Ca（2+）触发的细胞死亡，与对照组相比，但不影响星孢菌素或衣霉素介导的细胞死亡。这些结果表明 γ-分泌酶活性在 Ca（2+）介导的细胞死亡中起作用。
