Simvastatin alters membrane cholesterol distribution and beta-amyloid levels in brains of female APP751SL mice.

Statins (HMG-CoA reductase or CSE-inhibitors) strongly reduce the cellular amyloid-beta protein production by modulating the processing of amyloid precursor protein (APP) in vitro. Several in vivo studies have addressed this important issue in transgenic mouse models with inconsistent results. Recently, we showed that simvastatin alters cholesterol distribution in synaptosomal membranes (SPM) in vivo. In the present study, we tested whether these changes in cholesterol membrane distribution affect APP-processing in vivo. Female APP751SL mice were force-fed with simvastatin (50 mg/kg b.wt.) by oral gavage over a time period of 3 weeks. Our data show that chronic simvastatin treatment decreased cholesterol levels in the brain and affected cholesterol distribution within SPM. Simvastatin significantly increased the levels of insoluble Abeta1-40 and Abeta1-42 but reduced levels of soluble Abeta1-40 in the brain. The reduction of soluble Abeta1-40 levels in the brain was associated with an increase of plasma-levels of AP31.40 in simvastatin-treated animals that may indicate enhanced Abeta1-40-clearance from the brain. Although the observed alteration in transbilayer cholesterol is likely to be involved in changes of APP processing by alpha-, beta- and gamma-secretase, we cannot exclude other potential mechanisms of statins such as lipid and non-lipid related, pleiotropic effects. Our data were evaluated in reference to published studies and a possible gender effect was identified.