Dose-specific effect of simvastatin on hypoxia-induced HIF-1α and BACE expression in Alzheimer's disease cybrid cells.

Jin-Heon Jeong,Manho Kim,Jun Young Chang,Jin-Young Ahn,Moon-Ku Han,Paul A Lapchak,Kyu Sun Yum,Sangyun Kim

doi:10.1186/s12883-015-0390-5

Abstract

BackgroundAlzheimer’s disease (AD) is associated with vascular risk factors; brain ischemia facilitates the pathogenesis of AD. Recent studies have suggested that the reduction of AD risk with statin was achieved by decreased amyloidogenic amyloid precursor protein.MethodsWe used mitochondrial transgenic neuronal cell (cybrid) models to investigate changes in the levels of intracellular hypoxia inducible factor 1α (HIF-1α) and β-site amyloid precursor protein cleaving enzyme (BACE) in the presence of simvastatin. Sporadic AD (SAD) and age-matched control (CTL) cybrids were exposed to 2 % O2 and incubated with 1 μM or 10 μM simvastatin.ResultsThere was no significant difference between cell survival by 1 or 10 μM simvastatin in both SAD and CTL cybrids. In the presence of 1 μM simvastatin, intracellular levels of HIF-1α and BACE decreased by 40–70 % in SAD, but not CTL cybrids. However, 10 μM simvastatin increased HIF-1α and BACE expression in both cybrid models.ConclusionOur results suggest demonstrate differential dose-dependent effects of simvastatin on HIF-1α and BACE in cultured Alzheimer’s disease cybrid cells.

Highlights

Alzheimer’s disease (AD) is associated with vascular risk factors; brain ischemia facilitates the pathogenesis of AD
After treatment with 1 μM simvastatin, hypoxia inducible factor 1α (HIF-1α) and β-site amyloid precursor protein cleaving enzyme (BACE) levels decreased in the Sporadic AD (SAD) cybrids (Fig. 2a, 2b)
The reduction in HIF-1α expression was prominent at 3 h, and the reduction in BACE expression was pronounced at 12 h

Summary

Introduction

Alzheimer’s disease (AD) is associated with vascular risk factors; brain ischemia facilitates the pathogenesis of AD. Alzheimer’s disease (AD) is a progressive neurodegenerative disorder that affects memory function; it is characterized by the formation of senile plaques composed of beta amyloid (Aβ) [1]. Vascular risk factors such as hypertension and diabetes mellitus have an established association with AD, and over 30 % of AD patients show evidence of cerebral infarcts [2, 3]. The neuroprotective properties of statins have been demonstrated in models of cerebral ischemia [8] Beyond their originally defined role in lowering cholesterol, statins have been used to manage neurodegenerative disorders such as vascular dementia and AD [9], because they can improve vascular integrity. The effects of statin differed according to dose; low-dose simvastatin decreases Aβ production without increment of Aβ release [15]

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Discussion

Conclusion