Activation of PERK Signaling Attenuates A[beta]-Mediated ER Stress

• Published in: PloS one 2010-05, Vol.5 (5), p.e10489
• Main Authors: Lee, Do Yeon, Lee, Kyu-Sun, Lee, Hyun Jung, Kim, Do Hee, Noh, Yoo Hun, Yu, Kweon, Jung, Hee-Yeon, Lee, Sang Hyung, Lee, Jun Young, Youn, Young Chul, Jeong, Yoonhwa, Kim, Dae Kyong, Lee, Won Bok, Kim, Sung Su
• Format: Article
• Language: English
• Subjects: Alzheimer's disease; Apoptosis; Care and treatment; Nervous system diseases; Neurons; Proteins; Stress (Physiology); Target marketing
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0010489

Alzheimer's disease (AD) is characterized by the deposition of aggregated beta-amyloid (A[beta]), 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 A[beta] neurotoxicity still remain unknown. Here, we show that treatment of A[beta] triggers the UPR in the SK-N-SH human neuroblastoma cells. A[beta] mediated UPR pathway accompanies the activation of protective pathways such as Grp78/Bip and PERK-eIF2[alpha] pathway, as well as the apoptotic pathways of the UPR such as CHOP and caspase-4. Knockdown of PERK enhances A[beta] neurotoxicity through reducing the activation of eIF2[alpha] and Grp8/Bip in neurons. Salubrinal, an activator of the eIF2[alpha] pathway, significantly increased the Grp78/Bip ER chaperone resulted in attenuating caspase-4 dependent apoptosis in A[beta] treated neurons. These results indicate that PERK-eIF2[alpha] pathway is a potential target for therapeutic applications in neurodegenerative diseases including AD.