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Endoplasmic reticulum stress occurs downstream of NR2B subunit of N-methyl-D-aspartate receptor in mature hippocampal cultures treated with amyloid-β oligomers

Costa, R.O. and Lacor, P.N. and Ferreira, I.L. and Auberson, Yves and Klein, W.L. and Oliveira, C.R. and 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

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