Reduction of A by fluvastatin associates with altered levels of APP and of BACE1 and ADAM10 mRNA, independent of brain total cholesterol in rats

The aim of the present study was to determine the effects of fluvastatin, a relatively hydrophilic 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGR) inhibitor, on endogenous amyloid beta (Aβ) production and if such effects would be associated with changes in brain total cholesterol in rats. Wistar male rats were treated with fluvastatin at a dose of 20 mg/kg/day or vehicle (controls) by oral gavage for 28 days. We examined serum and brain cholesterol levels by CHOD-PAP method, brain Aβ levels by radioimmunoassay, mRNA levels of HMGR and cholesterol 24S-hydroxylase (CYP46) involving in cholesterol balance, β-secretase (BACE1) and α-secretase (ADAM10) involving in amyloid beta precursor protein (AβPP) processing by RT-PCR and protein levels of AβPP by immunohistochemistry. Serum total cholesterol and brain Aβ levels were significantly reduced in fluvastatin-treated rats. There was no change in total cholesterol levels, HMGR and CYP46 mRNA levels in the brain of fluvastatin-treated rats. Fluvastatin reduced AβPP protein levels and up-regulated ADAM10 but down-regulated BACE1 mRNA expression in rat brain under used condition. These results suggest that reduction of brain Aβ levels by fluvastatin is associated with changes in level of AβPP and AβPP cleavage-related enzyme mRNA, and is independent of brain total cholesterol. It may contribute to one of neuroprotective effects of fluvastatin and reveal that administration of fluvastatin could be beneficial in the preventation of AD.   Key words: Alzheimer’s disease, cholesterol, amyloid β, amyloid-β protein precursor, fluvastatin, statin.