Costa, R.O., Lacor, P.N., Ferreira, I.L., Auberson, Yves, Klein, W.L., Oliveira, C.R., Rego, A.C. and Pereira, C.M.F. (2012) Endoplasmic reticulum stress occurs downstream of NR2B subunit of N-methyl-D-aspartate receptor in mature hippocampal cultures treated with amyloid-β oligomers. Aging Cell.

Abstract

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder affecting both the hippocampus and the cerebral cortex. Reduced synaptic density that occurs early in the disease process seems to be partially due to the overactivation of N-methyl-D-aspartate receptors (NMDARs) leading to excitotoxicity. Recently, we demonstrated that amyloid-beta oligomers (AO), the species implicated in synaptic loss during the initial disease stages, induce endoplasmic reticulum (ER) stress in cultured cortical neurons. Here, we investigated whether AO trigger ER stress by an NMDAR-dependent mechanism leading to hippocampal dysfunction and analyzed the contribution of NR2A and NR2B subunits of NMDAR. Our data revealed that AO induce ER stress in mature hippocampal cultures, activating ER stress-associated sensors and increasing the levels of the ER chaperone GRP78. We also showed that AO treatment induces NADPH oxidase (NOX)-mediated superoxide production downstream of NR2B and impairs ER and cytosolic Ca2+ homeostasis. These events precede changes in cell viability and activation of the ER stress-mediated apoptotic pathway, occurring by a caspase-12-independent mechanism. Moreover, AO-mediated ER stress was characterized by increased nuclear levels of the transcription factor GADD153/CHOP. Significantly, ER stress took place after AO interaction with NR2B subunits. In addition, AO-induced ER stress and hippocampal dysfunction was prevented by pre-incubation with ifenprodil, an antagonist of NR2B subunits while the NR2A antagonist NVP-AAM077 only slightly attenuated AO-induced neurotoxicity. Taken together, our results highlight the role of NR2B subunit of NMDARs on ER stress-mediated hippocampal dysfunction caused by AO suggesting that it can be a potential therapeutic target during the early stages of AD.

Item Type:	Article
Keywords:	Endoplasmic reticulum, Alzheimer’s disease, amyloid-β oligomers, NMDARs
Date Deposited:	26 Apr 2016 23:46
Last Modified:	26 Apr 2016 23:46
URI:	https://oak.novartis.com/id/eprint/4649