Differential signaling of unfolded protein responses (UPR) and endoplasmic reticulum (ER) stress in neurons exposed to β-amyloid peptide

Abstract

Accumulation of β-amyloid (Aβ) peptide has long been considered as one of the toxic factors contributing to the progression of neurodegeneration in Alzheimer’s disease (AD). It has previously been demonstrated that Aβ peptide triggers release of calcium from the ER. Since calcium plays important roles in the proper folding of protein in the ER, depletion of ER calcium has been considered to be a factor inducing UPR. The aim of this study is to examine the signaling mechanisms of UPR. While Aβ peptide induced calcium release from the ER in primary cultured cortical neurons, it could not stimulate the phosphorylation of PKR-like ER kinase (PERK). In addition, no alternative splicing of Xbp1 mRNA or upregulation of its mRNA were detected suggesting that no activation of ATF6 and Ire1 in neurons exposed to Aβ peptide. Although UPR is not observed, increased protein levels of Grp78, mRNA levels of Gadd153, cleavage of caspase-12 and activity of caspase-7 were detected 16 h after exposure to Aβ peptide. The results suggest that signaling of UPR and ER stress responses can be two separated events. While neuronal apoptosis occurred prior to the signaling of ER stress response, ER stress responses are not the early apoptotic events mediating neuronal apoptosis. Supported by Procore-France/Hong Kong Joint Research Scheme (F-HK21/03T) to RCCC & JH ; HKU Seed Funding for Basic Research (2004) to RCCC