Abstract
Backgroundβ-Amyloid protein (Aβ) has been shown to potentiate the caspase-3 activation induced by the commonly used inhalation anesthetic isoflurane. However, it is unknown whether reduction in Aβ levels can attenuate the isoflurane-induced caspase-3 activation. We therefore set out to determine the effects of RNA interference-mediated silencing of amyloid precursor protein (APP) and β-site APP-cleaving enzyme (BACE) on the levels of Aβ and the isoflurane-induced caspase-3 activation.MethodsH4 human neuroglioma cells stably transfected to express full-length human APP (H4-APP cells) were treated with small interference RNAs (siRNAs) targeted at silencing BACE and APP for 48 hours. The cells were then treated with 2% isoflurane for six hours. The levels of BACE, APP, and caspase-3 were determined using Western blot analysis. Sandwich Enzyme-linked immunosorbent assay (ELISA) was used to determine the extracellular Aβ levels in the conditioned cell culture media.ResultsHere we show for the first time that treatment with BACE and APP siRNAs can decrease levels of BACE, full-length APP, and APP c-terminal fragments. Moreover, the treatment attenuates the Aβ levels and the isoflurane-induced caspase-3 activation. These results further suggest a potential role of Aβ in the isoflurane-induced caspase-3 activation such that the reduction in Aβ levels attenuates the isoflurane-induced caspase-3 activation.ConclusionThese findings will lead to more studies which aim at illustrating the underlying mechanism by which isoflurane and other anesthetics may affect Alzheimer's disease neuropathogenesis.
Highlights
Alzheimer’s disease (AD), one of the most common forms of dementia, affects 4.5 million Americans and costs more than $100 billion a year on direct care alone
The b-site APP-cleaving enzyme (BACE) small interference RNAs (siRNAs) treatment attenuates the isoflurane-induced caspase-3 activation in the H4-amyloid precursor protein (APP) cells. These results have suggested that decreased Ab levels by the RNA interference (RNAi)-mediated silencing of BACE may lead to the attenuation of the isofluraneinduced caspase-3 activation
In conclusion, we have found that RNAi-mediated silencing of either BACE or APP can lead to a reduction in Ab levels as well as an attenuation in the isofluraneinduced caspase-3 activation
Summary
Alzheimer’s disease (AD), one of the most common forms of dementia, affects 4.5 million Americans and costs more than $100 billion a year on direct care alone. Increasing evidence suggests a role for caspase activation and apoptosis in AD neuropathogenesis [[4,5,6,7,8,9,10,11,12,13], reviewed in [14,15]]. There has been debate in regards to the contribution of apoptosis to neuronal loss in AD because the apoptotic markers are rarely detected in the brain of AD patients [reviewed in [16,17]]. This could be due to the long duration of AD and very rapid clearance of apoptotic cells from organs. Activated caspase-6 and caspase-9 have been detected in AD brains [25,26]
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