Famer Daniel, Crisby Milita
Neurotec Department, Division of Clinical and Experimental Geriatrics, Karolinska Institutet, Karolinska University Hospital Huddinge, SE-14186 Stockholm, Sweden.
Neurosci Lett. 2004 Nov 23;371(2-3):209-14. doi: 10.1016/j.neulet.2004.08.069.
An increasing number of studies suggest that disturbances in cholesterol homeostasis may promote the formation and deposition of beta-amyloid (A beta) and the progression of Alzheimer's disease (AD). In this paper, we have analyzed the effect of the lipid-lowering compound rosuvastatin on apoptosis and caspase-3 activity in human neuroblastoma SH-SY5Y cells. Exposure of SH-SY5Y cells to A beta(1-42) alone resulted in a significantly increased caspase-3 activity approximately by 35% (135+/-15%, p<0.05), and decreased alpha-secretase activity by 34% (67.4+/-2.7%, p<0.001) compared to the controls (100+/-18.1%). Rosuvastatin alone decreased caspase-3 activity by 15% (85.3+/-1.5%, p<0.0005) compared to the controls and by 50% to cells exposed to A beta alone (p<0.00005). Cells exposed to rosuvastatin alone had a higher alpha-secretase activity compared to cells exposed to A beta (76.4+/-23.8%, n.s.) but a slightly lower activity compared to the controls (n.s.). Pre-treatment of SY-SY5Y cells with rosuvastatin prior to incubation with A beta(1-42) resulted in decreased caspase-3 activity by approximately 15% compared to the controls and by approximately 48% (86.8+/-16.9%, p<0.05) compared to cells treated with A beta(1-42) alone. Also, alpha-secretase activity was increased by approximately 50% compared to the controls and by 84% (151.3+/-10.1%, p<0.05), compared to cells treated with A beta(1-42) alone. Mevalonate abrogated the effect of rosuvastatin in vitro. To our knowledge, this is the first study demonstrating that the hydrophilic compound rosuvastatin decreases caspase-3 activity and increases alpha-secretase activity in human neuroblastoma SH-SY5Y cells exposed to A beta in vitro. These effects are essential for modulation of the amyloidogenic pathway and mediators of apoptosis in AD.
越来越多的研究表明，胆固醇稳态紊乱可能促进β-淀粉样蛋白（Aβ）的形成和沉积以及阿尔茨海默病（AD）的进展。在本文中，我们分析了降脂化合物瑞舒伐他汀对人神经母细胞瘤SH-SY5Y细胞凋亡和半胱天冬酶-3活性的影响。单独将SH-SY5Y细胞暴露于Aβ（1-42）会导致半胱天冬酶-3活性显著增加约35%（135±15%，p<0.05），与对照组（100±18.1%）相比，α-分泌酶活性降低34%（67.4±2.7%，p<0.001）。与对照组相比，单独使用瑞舒伐他汀可使半胱天冬酶-3活性降低15%（85.3±1.5%，p<0.0005），与单独暴露于Aβ的细胞相比降低50%（p<0.00005）。与暴露于Aβ的细胞相比，单独暴露于瑞舒伐他汀的细胞具有更高的α-分泌酶活性（76.4±23.8%，无显著性差异），但与对照组相比活性略低（无显著性差异）。在与Aβ（1-42）孵育之前，先用瑞舒伐他汀预处理SY-SY5Y细胞，与对照组相比，半胱天冬酶-3活性降低约15%，与单独用Aβ（1-42）处理的细胞相比降低约48%（86.8±16.9%，p<0.05）。此外，与对照组相比，α-分泌酶活性增加约50%，与单独用Aβ（1-42）处理的细胞相比增加84%（151.3±10.1%，p<0.05）。甲羟戊酸消除了瑞舒伐他汀在体外的作用。据我们所知，这是第一项证明亲水性化合物瑞舒伐他汀在体外可降低暴露于Aβ的人神经母细胞瘤SH-SY5Y细胞中半胱天冬酶-3活性并增加α-分泌酶活性的研究。这些作用对于调节AD中的淀粉样蛋白生成途径和细胞凋亡介质至关重要。
