Activation of PERK Signaling Attenuates A beta-Mediated ER Stress

Abstract

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.