title: Activation of PERK signaling attenuates Abeta-mediated ER stress.
abstract: Alzheimer's disease (AD) is characterized by the deposition of aggregated beta-amyloid (Abeta), which triggers a cellular stress response called the unfolded protein response (UPR). The UPR signaling pathway is a cellular defense system for dealing with the accumulation of misfolded proteins but switches to apoptosis when endoplasmic reticulum (ER) stress is prolonged. ER stress is involved in neurodegenerative diseases including AD, but the molecular mechanisms of ER stress-mediated Abeta neurotoxicity still remain unknown. Here, we show that treatment of Abeta triggers the UPR in the SK-N-SH human neuroblastoma cells. Abeta mediated UPR pathway accompanies the activation of protective pathways such as Grp78/Bip and PERK-eIF2alpha pathway, as well as the apoptotic pathways of the UPR such as CHOP and caspase-4. Knockdown of PERK enhances Abeta neurotoxicity through reducing the activation of eIF2alpha and Grp8/Bip in neurons. Salubrinal, an activator of the eIF2alpha pathway, significantly increased the Grp78/Bip ER chaperone resulted in attenuating caspase-4 dependent apoptosis in Abeta treated neurons. These results indicate that PERK-eIF2alpha pathway is a potential target for therapeutic applications in neurodegenerative diseases including AD.
authors.affiliation: Department of Anatomy and Cell Biology, College of Medicine, Chung-Ang University, Seoul, Korea.
authors.forename: Do Yeon
authors.initials: DY
authors.lastname: Lee
authors.forename: Kyu-Sun
authors.initials: KS
authors.lastname: Lee
authors.forename: Hyun Jung
authors.initials: HJ
authors.lastname: Lee
authors.forename: Do Hee
authors.initials: DH
authors.lastname: Kim
authors.forename: Yoo Hun
authors.initials: YH
authors.lastname: Noh
authors.forename: Kweon
authors.initials: K
authors.lastname: Yu
authors.forename: Hee-Yeon
authors.initials: HY
authors.lastname: Jung
authors.forename: Sang Hyung
authors.initials: SH
authors.lastname: Lee
authors.forename: Jun Young
authors.initials: JY
authors.lastname: Lee
authors.forename: Young Chul
authors.initials: YC
authors.lastname: Youn
authors.forename: Yoonhwa
authors.initials: Y
authors.lastname: Jeong
authors.forename: Dae Kyong
authors.initials: DK
authors.lastname: Kim
authors.forename: Won Bok
authors.initials: WB
authors.lastname: Lee
authors.forename: Sung Su
authors.initials: SS
authors.lastname: Kim
mesh_terms: D016229:Amyloid beta-Peptides / Q000378:metabolism*; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002934:Cinnamates / Q000494:pharmacology; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology*; D000091342:Endoplasmic Reticulum Chaperone BiP; D004789:Enzyme Activation / Q000187:drug effects; D055785:Gene Knockdown Techniques; D006360:Heat-Shock Proteins / Q000378:metabolism; D006801:Humans; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000201:enzymology; D034741:RNA, Small Interfering / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013312:Stress, Physiological / Q000187:drug effects; D013890:Thiourea / Q000031:analogs & derivatives / Q000494:pharmacology; D056811:Unfolded Protein Response / Q000187:drug effects; D019892:eIF-2 Kinase / Q000378:metabolism*
chemical_list: D016229:Amyloid beta-Peptides; D002934:Cinnamates; D000091342:Endoplasmic Reticulum Chaperone BiP; D006360:Heat-Shock Proteins; D034741:RNA, Small Interfering; D013890:Thiourea; D019892:eIF-2 Kinase; C000717247:HSPA5 protein, human; C496827:salubrinal
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