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 Aβ1-40 and Aβ1-42 but reduced levels of soluble Aβ1-40 in the brain. The reduction of soluble Aβ1-40 levels in the brain was associated with an increase of plasma-levels of Aβ1-40 in simvastatin-treated animals that may indicate enhanced Aβ1-40-clearance from the brain. Although the observed alteration in transbilayer cholesterol is likely to be involved in changes of APP processing by α-, β- and γ-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.