Evaluation of endoplasmic reticulum stress in beta-amyloid peptide neurotoxicity

Abstract

One of the pathological hallmarks of Alzheimer’s disease (AD) is the accumulation of beta-amyloid (A ) peptide in the senile plaques. Therefore, A neurotoxicity is believed to play significant roles in AD. Mutation of presenilin-1 (PS- 1) gene sensitizes neurons to A toxicity and causes dysfunctions of endoplasmic reticulum (ER). Thus, ER stress is considered to be involved in AD pathogenesis. In this study, we aim to investigate different signaling pathways for ER stress responses in A neurotoxicity. Neurons exposed to A peptide did not elicit induction of alternative splicing in Xbp-1 mRNA by IRE-1, up-regulation of Xbp-1 mRNA by ATF-6 and PERK phosphorylation. There were inductions of GRP 78 and GADD153 as well as activation of caspase-12 and caspase-7 after 16-h incubation of A peptide. The results suggested that ER stress is not an early event involved in A neurotoxicity. Activation of JNK and phosphorylation of eIF2 were found at early time-point. However, these signaling events and neuronal cell death were not mediated by ER stress responses. Taken together, ER stress seems to be a late response in A peptide-induced toxicity. Acknowledgements: This work is supported by HKU Seed Funding for Basic Research (202-2003) to RCCC and is a part for Area of Excellence (AoE/P-10/01).