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

Accumulation of amyloid β-peptide (Aβ) 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 Aβ neurotoxicity has never been explored. The present study was therefore undertaken to test whether sestrin2 may be induced by Aβ and its possible role in modulating Aβ neurotoxicity. We showed that sestrin2 expression was elevated in primary rat cortical neurons upon Aβ 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 Aβ 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 Aβ that was accompanied by more severe neuronal death. Inhibition of autophagy by bafilomycin A1 also enhanced Aβ neurotoxicity. Together, these results indicate that sestrin2 induced by Aβ plays a protective role against Aβ neurotoxicity through, at least in part, regulation of autophagy.