N-methyl-D-aspartate receptor-mediated calcium overload and endoplasmic reticulum stress are involved in interleukin-1beta-induced neuronal apoptosis in rat hippocampus

Increased levels of interleukin (IL)-1β and its gene expression are implicated in the etiology of Alzheimer's disease (AD). IL-1β activates microglia and stimulates glutamatergic N-methyl-D-aspartate receptor NMDA receptor expression, thereby disturbing intracellular Ca^2 + homeostasis. Ca^2 + disequilibrium, in turn, may trigger endoplasmic reticulum (ER) stress, contributing to overall excitotoxicity and neuronal death that evoke AD. However, it is unclear whether IL-1β-induced neuronal apoptosis is mediated by the glutamatergic system, ER stress and/or Ca^2 + dysfunction. The present study investigated the role of NMDA receptor (NMDAR) in ER stress and IL-1β-evoked neuronal death by assessing NMDAR-induced Ca^2 + overload and NMDA-mediated ER stress. Male Long Evans rats were treated with IL-1β (with or without NMDAR antagonist MK801) injected intracerebroventricularly for 8 days. Glutamate concentration was measured by HPLC, and mRNA and protein expression of microglial biomarkers and NMDAR, as well as markers of Ca^2 + overload (caplain2) and ER stress (glucose-regulated protein 78, GRP78, and C/EBP homologous protein-10, CHOP), were assessed by real-time PCR and western blot. Apoptosis was also evaluated in the hippocampal neurons using TUNEL. Overall, IL-1β induced robust neuronal apoptosis, accompanied by upregulated NMDAR, caplain2, GRP78 and CHOP. MK801 pretreatment significantly attenuated neuronal apoptosis and NMDA up-regulation, also reducing GRP78 and CHOP expression. In summary, these results suggest that IL-1β may disturb intracellular Ca^2 + homeostasis via NMDAR-mediated mechanism, thereby triggering neuronal apoptosis by enhancing ER stress.