Statins Reduce Amyloid β-Peptide Production by Modulating Amyloid Precursor Protein Maturation and Phosphorylation Through a Cholesterol-Independent Mechanism in Cultured Neurons
2013
Statins,
3-hydroxy-3-methylglutaryl-coenzymeA (
HMG-CoA)
reductaseinhibitors, have been reported to attenuate amyloid-β peptide (Aβ) production in various
cellular models. However, the mechanisms by which
statinsaffect neuronal Aβ production have not yet been clarified. Here, we investigated this issue in rat primary cortical neurons using two
statins,
pitavastatin(PV) and atorvastatin (AV). Treatment of neurons with 0.2–2.5 μM PV or AV for 4 days induced a concentration- and time-dependent reduction in the secretion of both Aβ40 and Aβ42. Moreover, Western blot analyses of cell lysates showed that treatment with PV or AV significantly reduced expression levels of the mature form of amyloid precursor protein (APP) and Thr668-phosphorylated APP (P-APP), but not immature form of APP; the decreases in P-APP levels were more notable than those of mature APP levels. The
statintreatment did not alter expression of
BACE1(β-site APP-cleaving enzyme 1) or γ-secretase complex proteins (
presenilin1,
nicastrin,
APH-1, and
PEN-2). In neurons overexpressing APP via recombinant adenoviruses, PV or AV similarly reduced Aβ secretion and the levels of mature APP and P-APP.
Statinsalso markedly reduced cellular cholesterol content in neurons in a concentration-dependent manner. Co-treatment with mevalonate reversed the
statin-induced decreases in Aβ secretion and mature APP and P-APP levels, whereas co-treatment with cholesterol did not, despite recovery of cellular cholesterol levels. Finally, cell-surface biotinylation experiments revealed that both
statinssignificantly reduced the levels of cell-surface P-APP without changing those of cell surface mature APP. These results suggest that
statinsreduce Aβ production by selectively modulating APP maturation and phosphorylation through a mechanism independent of cholesterol reduction in cultured neurons.
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