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A specific inhibitor of cholesterol biosynthesis, BM15.766, reduces the expression of β‐secretase and the production of amyloid‐β in vitro
Author(s) -
Parsons Richard B.,
Subramaniam Daryl,
Austen Brian M.
Publication year - 2007
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/j.1471-4159.2007.04619.x
Subject(s) - cholesterol , biosynthesis , biochemistry , golgi apparatus , simvastatin , chemistry , prenylation , amyloid precursor protein , microbiology and biotechnology , in vitro , enzyme , biology , cell , medicine , pharmacology , alzheimer's disease , disease
We have previously shown that statins reduce the production of amyloid‐β (Aβ) 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 Aβ. Incubation of cells with the specific cholesterol biosynthesis inhibitor BM15.766 together with 50 μmol/L simvastatin and 400 μmol/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 Aβ production ( r = 0.9683, p = 0.0317). A total of 2.5 μmol/L BM15.766 inhibited the dimerisation of BACE, whilst the expression of BACE monomer was reduced by 5 μmol/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 Aβ production without reducing protein isoprenylation.