Rosuvastatin reduces caspase-3 activity and up-regulates alpha-secretase in human neuroblastoma SH-SY5Y cells exposed to A beta.
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.
Famer
Daniel
D
Neurotec Department, Division of Clinical and Experimental Geriatrics, Karolinska Institutet, Karolinska University Hospital Huddinge, SE-14186 Stockholm, Sweden.
Crisby
Milita
M
D053829:Amyloid Precursor Protein Secretases; D016229:Amyloid beta-Peptides / Q000494:pharmacology*; D016282:Aspartic Acid Endopeptidases; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D010450:Endopeptidases / Q000096:biosynthesis*; D004789:Enzyme Activation / Q000187:drug effects / Q000502:physiology; D005464:Fluorobenzenes / Q000494:pharmacology*; D006801:Humans; D009447:Neuroblastoma / Q000201:enzymology*; D011743:Pyrimidines / Q000494:pharmacology*; D000068718:Rosuvastatin Calcium; D013449:Sulfonamides / Q000494:pharmacology*; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology
D016229:Amyloid beta-Peptides; D005464:Fluorobenzenes; D011743:Pyrimidines; D013449:Sulfonamides; D000068718:Rosuvastatin Calcium; D053829:Amyloid Precursor Protein Secretases; D010450:Endopeptidases; C505407:CASP3 protein, human; D053148:Caspase 3; D020169:Caspases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human