Statin effect on the expression of HIF-1α and BACE in Alzheimers disease cybrid cells under hypoxia

Abstract

Background: Alzheimers disease (AD) is a progressive neurodegenerative disorder affecting memory function and higher cognitive function. Vascular risk factors have an established association with AD, and brain ischemia facilitates the pathogenesis of AD by accumulating beta amyloid (Aβ). Hypoxia increases the expression of β-site amyloid precursor protein cleaving enzyme (BACE) through overexpression of hypoxia inducible factor 1α (HIF-1α), resulting in accumulation of Aβ. Statins (HMG-CoA reductase inhibitor) have protective effects against hypoxia, and long-term statin treatment is known to decrease the risk of developing AD. Methods and Results: In this study, we used mitochondrial transgenic neuronal cell (cybrid) models to investigate the changes of intracellular HIF-1α and BACE levels with administration of statins under hypoxia. Sporadic AD (SAD) cybrids and age-matched control (CTL) cybrids were incubated under hypoxia (93% N2/5% CO2/2% air), and then 1 μM or 10 μM simvastatin was administrated. Intracellular HIF-1α and BACE levels were measured using Western-blot analysis. Under hypoxia, CTL and SAD cybrids showed reduced viability over time, and the intracellular expression of HIF-1α and BACE was increased. After administration of 1 μM simvastatin, the intracellular levels of HIF-1α and BACE were decreased in SAD cybrids. With 10 μM simvastatin, the intracellular expression of HIF-1α and BACE was increased in both SAD and CTL cybrids. Conclusion: A low-dose statin reduces the expression of HIF-1α and BACE under hypoxia in SAD cybrids. In contrast, a high-dose statin aggravates the expression of HIF-1α and BACE in both SAD and CTL cybrids. These results suggest that low-dose statins are more beneficial than high-dose statins in the prevention of Aβ production.