Induction of sestrin2 as an endogenous protective mechanism against amyloid beta-peptide neurotoxicity in primary cortical culture

Accumulation of amyloid beta-peptide (A beta) in senile plaques, a pathological hallmark of Alzheimer's disease (AD), has been implicated in neurodegeneration. Recent studies suggested sestrin2 as a crucial mediator for reactive oxygen species (ROS) scavenging and autophagy regulation that both play a pivotal role in age-dependent neurodegenerative diseases. However, the potential link between sestrin2 and A beta neurotoxicity has never been explored. The present study was therefore undertaken to test whether sestrin2 may be induced by A beta and its possible role in modulating A beta neurotoxicity. We showed that sestrin2 expression was elevated in primary rat cortical neurons upon A beta exposure; a heightened extent of sestrin2 expression was also detected in the cortices of 12-month-old APPswe/PSEN1dE9 transgenic mice. Exposure of cortical neurons to A beta led to formation of LC3B-II, an autophagic marker; an increased LC3B-II level was also observed in the cortices of 12-month-old AD transgenic mice. More importantly, downregulation of sestrin2 by siRNA abolished LC3B-II formation caused by A beta that was accompanied by more severe neuronal death. Inhibition of autophagy by bafilomycin A1 also enhanced A beta neurotoxicity. Together, these results indicate that sestrin2 induced by A beta plays a protective role against A beta neurotoxicity through, at least in part, regulation of autophagy. (C) 2013 Elsevier Inc. All rights reserved.