Simvastatin elevates anti-apoptotic Bcl–2 levels in guinea pig brain

In guinea pigs simvastatin decreases Ab levels without affecting brain cholesterol. Guinea pigs are established models to investigate hypercholesterolemia and statin effects. Like humans, guinea pigs carry the majority of cholesterol in the LDL fraction and develop atherosclerosis when challenged with hypercholesterolemic diets. In the present study we focused on brain synaptosomal plasma membranes (SPM), the relevant target for signal transduction processes and Ab generation. We confirmed that simvastatin treatment affects cholesterol levels neither in brain homogenate nor in SPM of guinea pigs. However, HMG-CoA reductase mRNA and protein levels were significantly enhanced in brains of simvastatin treated guinea pigs indicating a compensatory up-regulation of the enzyme. Accordingly, brain HMG-CoA reductase activity was significantly elevated after simvastatin wash out. This clearly indicates pharmacological effects of simvastatin in the brain. Inhibition of HMG-CoA reductase also accounts for cholesterol-independent effects of statins. Using a mouse model, we recently identified anti-apoptotic Bcl–2 as a new target of simvastatin in the brain (JPET 312(2005)786). Herein, we confirm that simvastatin treatment enhances Bcl–2 protein levels in guinea pig brain. In conclusion, the impact of statins on cholesterol levels and Ab generation remains unclear, but our data clearly indicate pleiotropic effects of statins in brain.