Lack of early activation of endoplasmic reticulum stress in beta-amyloid neurotoxicity

Abstract

Beta-amyloid (Ab) peptide neurotoxicity plays significant roles in Alzhei-mer’s disease (AD). Mutation of presenilin-1 (PS-1) gene sensitizes neuronsto Ab toxicity, also, causes dysfunctions of endoplasmic reticulum (ER).Therefore, ER stress receives increasing attention to AD. This study aimed toinvestigate different signaling pathways for ER stress responses in Abneurotoxicity. Rat cortical neurons exposed to Ab peptide did not showedinduction of alternative splicing in Xbp-1 mRNA by IRE-1, up-regulation of Xbp-1 mRNA by ATF-6 and PERK phosphorylation. After 16-h treatment ofAb peptide, there were induction of GRP 78 and GADD153 as well asactivation of caspase-12 and -7. These data suggested that ER stress is not anearly event involved in Ab neurotoxicity. Activation of JNK andphosphorylation of eIF2a were found at early time-point, however, thesesignaling events and neuronal cell death were not mediated by ER stressresponses. Taken together, ER stress seems to be a late response in Abpeptide-induced toxicity.