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Activation of PERK signaling attenuates Abeta-mediated ER stress.

Lee do Y, Lee KS, Lee HJ, Kim do H, Noh YH, Yu K, Jung HY, Lee SH, Lee JY, Youn YC, Jeong Y, Kim DK, Lee WB, Kim SS - PLoS ONE (2010)

Bottom Line: Here, we show that treatment of Abeta triggers the UPR in the SK-N-SH human neuroblastoma cells.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Anatomy and Cell Biology, College of Medicine, Chung-Ang University, Seoul, Korea.

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.

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Related in: MedlinePlus

PERK activator Salubrinal attenuates Aβ1-42-induced neuronal apoptosis through the regulation of Grp78/Bip and caspase-4.A, Salubrinal protects neuronal cells against Aβ1-42-induced cell death. Dose-dependent protection by Salubrinal of SK-N-SH cells treated with Aβ and various concentrations of Salubrinal as indicated. B, Co-treatment of Salubrinal and Aβ increased the neuronal cell viability compared with Aβ treatment. Caspase-4 (C) and -3 activity (D) induced by Aβ was suppressed by the co-treatment of Salubrinal and Aβ. Data were presented as means ± SD from at least three independent experiments. *P<0.05, control versus vehicle alone; #P<0.05, control versus Aβ alone.
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pone-0010489-g004: PERK activator Salubrinal attenuates Aβ1-42-induced neuronal apoptosis through the regulation of Grp78/Bip and caspase-4.A, Salubrinal protects neuronal cells against Aβ1-42-induced cell death. Dose-dependent protection by Salubrinal of SK-N-SH cells treated with Aβ and various concentrations of Salubrinal as indicated. B, Co-treatment of Salubrinal and Aβ increased the neuronal cell viability compared with Aβ treatment. Caspase-4 (C) and -3 activity (D) induced by Aβ was suppressed by the co-treatment of Salubrinal and Aβ. Data were presented as means ± SD from at least three independent experiments. *P<0.05, control versus vehicle alone; #P<0.05, control versus Aβ alone.

Mentions: To investigate whether Sal has the ability to prevent neuronal apoptosis induced by Aβ, we treated various concentration of Sal for 2 h before Aβ treatment and assessed cell viability using alamarBlue assay. While cell viability was decreased by treatment of Aβ, pre-treatment with Sal significantly attenuated Aβ-induced neuronal cell death from 25 µM. Pre-treatment with 100 µM Sal reduced Aβ-induced neuronal cell death by 36.3±2.8% (Fig. 4A and Figure S2). In addition, Aβ-mediated cell death was significantly reduced by pre-treatment with 100 µM Sal compared to Aβ treatment alone from 24 h (Fig. 4B).


Activation of PERK signaling attenuates Abeta-mediated ER stress.

Lee do Y, Lee KS, Lee HJ, Kim do H, Noh YH, Yu K, Jung HY, Lee SH, Lee JY, Youn YC, Jeong Y, Kim DK, Lee WB, Kim SS - PLoS ONE (2010)

PERK activator Salubrinal attenuates Aβ1-42-induced neuronal apoptosis through the regulation of Grp78/Bip and caspase-4.A, Salubrinal protects neuronal cells against Aβ1-42-induced cell death. Dose-dependent protection by Salubrinal of SK-N-SH cells treated with Aβ and various concentrations of Salubrinal as indicated. B, Co-treatment of Salubrinal and Aβ increased the neuronal cell viability compared with Aβ treatment. Caspase-4 (C) and -3 activity (D) induced by Aβ was suppressed by the co-treatment of Salubrinal and Aβ. Data were presented as means ± SD from at least three independent experiments. *P<0.05, control versus vehicle alone; #P<0.05, control versus Aβ alone.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2864758&req=5

pone-0010489-g004: PERK activator Salubrinal attenuates Aβ1-42-induced neuronal apoptosis through the regulation of Grp78/Bip and caspase-4.A, Salubrinal protects neuronal cells against Aβ1-42-induced cell death. Dose-dependent protection by Salubrinal of SK-N-SH cells treated with Aβ and various concentrations of Salubrinal as indicated. B, Co-treatment of Salubrinal and Aβ increased the neuronal cell viability compared with Aβ treatment. Caspase-4 (C) and -3 activity (D) induced by Aβ was suppressed by the co-treatment of Salubrinal and Aβ. Data were presented as means ± SD from at least three independent experiments. *P<0.05, control versus vehicle alone; #P<0.05, control versus Aβ alone.
Mentions: To investigate whether Sal has the ability to prevent neuronal apoptosis induced by Aβ, we treated various concentration of Sal for 2 h before Aβ treatment and assessed cell viability using alamarBlue assay. While cell viability was decreased by treatment of Aβ, pre-treatment with Sal significantly attenuated Aβ-induced neuronal cell death from 25 µM. Pre-treatment with 100 µM Sal reduced Aβ-induced neuronal cell death by 36.3±2.8% (Fig. 4A and Figure S2). In addition, Aβ-mediated cell death was significantly reduced by pre-treatment with 100 µM Sal compared to Aβ treatment alone from 24 h (Fig. 4B).

Bottom Line: Here, we show that treatment of Abeta triggers the UPR in the SK-N-SH human neuroblastoma cells.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Anatomy and Cell Biology, College of Medicine, Chung-Ang University, Seoul, Korea.

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.

Show MeSH
Related in: MedlinePlus