Statins are competitive inhibitors of HMG-CoA re- ductase, a rate-limiting enzyme for cholesterol synthesis, and have been widely used as plasma cholesterol lowering drugs in dyslipidemic patients. Many large-scale clinical intervention trials

Journal of Lipid Research Volume 50, 2009 2095 Copyright © 2009 by the American Society for Biochemistry and Molecular Biology, Inc. Statins are competitive inhibitors of HMG-CoA reductase, a rate-limiting enzyme for cholesterol synthesis, and have been widely used as plasma cholesterol lowering drugs in dyslipidemic patients. Many large-scale clinical intervention trials have demonstrated that statins signifi cantly lower morbidity and mortality, particularly due to reduction in cardiovascular events ( 1 ). Furthermore, numerous studies in recent years suggested that prolonged use of statins is associated with lower risk of other diseases, including dementia due to Alzheimer’s disease (AD) ( 2–6 ). These fi ndings led to recommendations for signifi cant increase in use of statins and prompted several clinical trials where statins were tested in people who already have AD. However, data published so far suggest that use of statins in AD patients led to mixed outcomes ( 7–12 ), somewhat diminishing the initial hope that statins may not only prevent processes leading to AD, but also retard the disease when it is already clinically apparent. Furthermore, a report by Algotsson and Winblad ( 13 ) suggested that patients with AD may have increased susceptibility to statininduced adverse effects. Additionally, although less often considered as an issue with use of statins, particularly those that cross the bloodbrain barrier (BBB) and blood-cerebrospinal fl uid (CSF) barrier, is the fact that some patients develop symptoms of dementia as a result of statin therapy, which improve or disappear upon statin withdrawal ( 14–16 ). These fi ndings are rarely reported, and many physicians tend to regard patient-reported memory impairment, particularly in the Abstract Inhibitors of HMG-CoA reductase (statins) are widely used medications for reduction of cholesterol levels. Statin use signifi cantly reduces risk of cardiovascular disease but has also been associated with lower risk of other diseases and conditions, including dementia. However, some reports suggest that statins also have detrimental effects on the brain. We provide evidence that simvastatin and pravastatin have signifi cantly different effects on expression of genes related to neurodegeneration in astrocytes and neuroblastoma (SK-N-SH) cells in culture. Simvastatin signifi cantly reduced expression of ABCA1 in astrocytes and neuroblastoma cells (by 79% and 97%, respectively; both P < 0.001). Pravastatin had a similar but attenuated effect on ABCA1 in astrocytes ( 54%, P < 0.001) and neuroblastoma cells ( 70%, P < 0.001). Simvastatin reduced expression of apolipoprotein E in astrocytes ( P < 0.01). Furthermore, both statins reduced expression of microtubule-associated protein tau in astrocytes ( P < 0.01), while both statins increased its expression in neuroblastoma cells ( P < 0.01). In SK-N-SH cells, simvastatin signifi cantly increased cyclin-dependent kinase 5 and glycogen synthase kinase 3 expression, while pravastatin increased amyloid precursor protein expression. Our data suggest that simvastatin and pravastatin differentially affect expression of genes involved in neurodegeneration and that statin-dependent gene expression regulation is cell type specifi c. —Dong, W., S. Vuletic, and J. J. Albers. Differential effects of simvastatin and pravastatin on expression of Alzheimer’s disease-related genes in human astrocytes and neuronal cells. 2009. J. Lipid Res. 50: 2095–2102.