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.
