title: Differential effects of simvastatin and pravastatin on expression of Alzheimer's disease-related genes in human astrocytes and neuronal cells.
abstract: Inhibitors of HMG-CoA reductase (statins) are widely used medications for reduction of cholesterol levels. Statin use significantly 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 significantly different effects on expression of genes related to neurodegeneration in astrocytes and neuroblastoma (SK-N-SH) cells in culture. Simvastatin significantly 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 significantly increased cyclin-dependent kinase 5 and glycogen synthase kinase 3beta 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 specific.
authors.affiliation: Northwest Lipid Metabolism and Diabetes Research Laboratories, University of Washington, Department of Medicine, Seattle, WA 98109, USA.
authors.forename: Weijiang
authors.initials: W
authors.lastname: Dong
authors.forename: Simona
authors.initials: S
authors.lastname: Vuletic
authors.forename: John J
authors.initials: JJ
authors.lastname: Albers
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism; D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism*; D001057:Apolipoproteins E / Q000235:genetics / Q000378:metabolism; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism*; D015153:Blotting, Western; D002478:Cells, Cultured; D004586:Electrophoresis; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D049294:Phospholipid Transfer Proteins / Q000235:genetics / Q000378:metabolism; D016133:Polymerase Chain Reaction; D017035:Pravastatin / Q000494:pharmacology*; D019821:Simvastatin / Q000494:pharmacology*; D016875:tau Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D018528:ATP-Binding Cassette Transporters; D001057:Apolipoproteins E; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; C054369:MAPT protein, human; D049294:Phospholipid Transfer Proteins; D016875:tau Proteins; D019821:Simvastatin; D017035:Pravastatin