Rosuvastatin reduces caspase-3 activity and up-regulates α-secretase in human neuroblastoma SH-SY5Y cells exposed to Aβ

An increasing number of studies suggest that disturbances in cholesterol homeostasis may promote the formation and deposition of beta-amyloid (Abeta) 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 Abeta(1-42) alone resulted in a significantly increased caspase-3 activity approximately by 35% (135 +/- 15%, p < 0.05), and decreased a-secretase activity by 34% (67.4 +/- 1 2.7%,p < 0.001) compared to the controls (100 +/- 18.1%). Rosuvastatin alone decreased caspase-3 activity by 15% (85.3 +/- 11.5%, p < 0.0005) compared to the controls and by 50% to cells exposed to Abeta alone (p < 0.00005). Cells exposed to rosuvastatin alone had a higher alpha-secretase activity compared to cells exposed to Abeta (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 Abeta(1-42) resulted in decreased caspase-3 activity by similar to15% compared to the controls and by similar to48% (86.8 +/- 16.9%, p < 0.05) compared to cells treated with Abeta(1-42) alone. Also, a-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 Abeta(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 a-secretase activity in human neuroblastoma SH-SY5Y cells exposed to Abeta in vitro. These effects are essential for modulation of the amyloidogenic pathway and mediators of apoptosis in AD. (C) 2004 Elsevier Ireland Ltd. All rights reserved.