title: Induction of sestrin2 as an endogenous protective mechanism against amyloid beta-peptide neurotoxicity in primary cortical culture.
abstract: 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.
authors.affiliation: Institute of Brain Science and Brain Research Center, National Yang-Ming University, Taipei, Taiwan.
authors.forename: Yueh-Sheng
authors.initials: YS
authors.lastname: Chen
authors.affiliation: Department of Neurology, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Taiwan; Center for Translational Research in Biomedical Sciences, Kaohsiung Chang Gung Memorial Hospital, Taiwan. Electronic address: chensd@adm.cgmh.org.tw.
authors.forename: Shang-Der
authors.initials: SD
authors.lastname: Chen
authors.affiliation: Institute of Brain Science and Brain Research Center, National Yang-Ming University, Taipei, Taiwan; Molecular Medicine Program, School of Life Sciences, National Yang-Ming University, Taipei, Taiwan.
authors.forename: Chia-Lin
authors.initials: CL
authors.lastname: Wu
authors.affiliation: Department of Pharmacology and Institute of Medicine, College of Medicine, Chung Shan Medical University, Taichung, Taiwan; Department of Pharmacy, Chung Shan Medical University Hospital, Taichung, Taiwan.
authors.forename: Shiang-Suo
authors.initials: SS
authors.lastname: Huang
authors.affiliation: Institute of Brain Science and Brain Research Center, National Yang-Ming University, Taipei, Taiwan. Electronic address: diyang@ym.edu.tw.
authors.forename: Ding-I
authors.initials: DI
authors.lastname: Yang
mesh_terms: D000544:Alzheimer Disease / Q000150:complications / Q000235:genetics; D016229:Amyloid beta-Peptides / Q000633:toxicity; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000818:Animals; D001930:Brain Injuries / Q000209:etiology / Q000378:metabolism / Q000517:prevention & control*; D002540:Cerebral Cortex / Q000187:drug effects* / Q000378:metabolism*; D004195:Disease Models, Animal; D004622:Embryo, Mammalian; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology*; D006801:Humans; D018942:Macrolides / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D009154:Mutation / Q000235:genetics; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D009924:Organ Culture Techniques; D010446:Peptide Fragments / Q000633:toxicity; D053764:Presenilin-1 / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors; D000084622:Sestrins
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D004791:Enzyme Inhibitors; D018942:Macrolides; D008869:Microtubule-Associated Proteins; D009687:Nuclear Proteins; D010446:Peptide Fragments; D053764:Presenilin-1; C508853:PSEN1 protein, human; C583887:Sesn2 protein, rat; D000084622:Sestrins; C075222:amyloid beta-protein (1-42); C074636:amyloid beta-protein (25-35); C057620:bafilomycin A
keywords: Alzheimer's disease; Amyloid β-peptide; Autophagy; Bafilomycin A1; LC3B; Sestrins