• Do Yeon Lee, Kyu-Sun Lee, Hyun Jung Lee, Kim Do Hee DH, Yoo Hun Noh, Kweon Yu, Hee-Yeon Jung, Sang Hyung Lee, Jun Young Lee, Young Chul Youn, Yoonhwa Jeong, Dae Kyong Kim, Won Bok Lee, and Sung Su Kim.
• Department of Anatomy and Cell Biology, College of Medicine, Chung-Ang University, Seoul, Korea.
• Plos One. 2010 May 5; 5 (5): e10489.

AbstractAlzheimer'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.

41 keywords...

hide…