Richard B Parsons, Daryl Subramaniam, Brian M Austen
Department of Basic Medical Sciences, St. Georges, University of London, Cranmer Terrace, London, UK. r.parsons@sgul.ac.uk
Journal of neurochemistry 2007 AugWe have previously shown that statins reduce the production of amyloid-beta (Abeta) 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 Abeta. Incubation of cells with the specific cholesterol biosynthesis inhibitor BM15.766 together with 50 micromol/L simvastatin and 400 micromol/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 Abeta production (r = 0.9683, p = 0.0317). A total of 2.5 micromol/L BM15.766 inhibited the dimerisation of BACE, whilst the expression of BACE monomer was reduced by 5 micromol/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 Abeta production without reducing protein isoprenylation.
Richard B Parsons, Daryl Subramaniam, Brian M Austen. A specific inhibitor of cholesterol biosynthesis, BM15.766, reduces the expression of beta-secretase and the production of amyloid-beta in vitro. Journal of neurochemistry. 2007 Aug;102(4):1276-91
PMID: 17472704
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