Differential effects of simvastatin and pravastatin on expression of Alzheimer's disease-related genes in human astrocytes and neuronal cells

Weijiang Dong, Simona Vuletic, and John J. Albers

Medicine, University of Washington, Seattle, WA 98109

Corresponding Author: jja{at}u.washington.edu

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 ATP binding cassette A1 (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 APOE in astrocytes (p<0.01). Furthermore, both statins reduced expression of microtubule associated protein tau (MAPT) 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 (CDK5) and glycogens synthase kinase 3ß (GSK3ß) expression, while pravastatin increased amyloid precursor protein (APP) 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.

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