Cholesterol distribution, not total levels, correlate with altered amyloid precursor protein processing in statin-treated mice

There are now a number of studies that suggest that cholesterol might regulate the processing of the amyloid precursor protein to form the neurotoxic peptide AΒ. This research has opened the possibility that cholesterol-lowering drugs might be efficacious as anti-AΒ drugs for use in Alzheimer's disease. The use of HMG-CoA reductase inhibitors (commonly called statins) in vitro and in vivo has proven them to be AΒ-lowering agents, however, the mechanism of action of these drugs is not yet known. One possible mechanism is that they reduce AΒ levels indirectly by reducing cholesterol in the central nervous system (CNS). In this study, we administered three different statins (simvastatin, lovastatin, and atorvastatin) to nontransgenic mice. We found that all three compounds had similar effects on AΒ, reducing both AΒ40 and AΒ42. The statins decreased Β-cleaved C-terminal fragment (CTF) although having no effect on α-CTF levels. However, the drugs did not have a similar effect on cholesterol in the CNS. Only lovastatin significantly reduced total cholesterol in isolated plasma membranes. As cholesterol is not distributed evenly in the plasma membrane, we examined bilayer distribution of cholesterol and found that all three statins caused CNS cholesterol to translocate from the cytofacial leaflet to the exofacial leaflet. This data suggests that cholesterol distribution and not total cholesterol levels may be important to AΒ production in the CNS.