A specific inhibitor of cholesterol biosynthesis, BM15.766, reduces the expression of β-secretase and the production of amyloid-β in vitro

We have previously shown that statins reduce the production of amyloid-beta (A beta) by both isoprenoid- and cholesterol-dependent mechanisms. These pathways contribute to the regulation of the dimerisation of BACE into its physiologically active form. Statins reduce cellular cholesterol levels by 20-40%; therefore, it is possible that the remaining cholesterol within the cell may play a significant role in the production of A beta. Incubation of cells with the specific cholesterol biosynthesis inhibitor BM15.766 together with 50 mu mol/L simvastatin and 400 mu mol/L mevalonate reduced cellular cholesterol levels in a dose-dependent manner with increasing BM15.766 concentration (r -0.9736, p = 0.0264). Furthermore, decreases in cellular cholesterol levels correlated with reductions in total AP production (r = 0.9683, p = 0.0317). A total of 2.5 mu mol/L BM15.766 inhibited the dimerisation of BACE, whilst the expression of BACE monomer was reduced by 5 mu mol/L BM15.766. BM15.766 treatment localised BACE predominantly within the Golgi, and reduced total BACE expression per cell. Similar changes were observed in the expression of the Golgi marker golgin-97, suggesting that reduced BACE expression may arise from a decrease in protein trafficking and an increase in degradation. By targeting cholesterol synthesis using specific cholesterol biosynthesis inhibitors, it is possible to reduce AP production without reducing protein isoprenylation.