Endoplasmic reticulum stress occurs downstream of GluN2B subunit of N-methyl-D-aspartate receptor in mature hippocampal cultures treated with amyloid-β oligomers

Aging Cell. 2012 Oct;11(5):823-33.

Rui O. Costa, Pascale N. Lacor, Ildete L. Ferreira, Rosa Resende, Yves P. Auberson, William L. Klein, Catarina R. Oliveira, Ana C. Rego and Cláudia M. F. Pereira

CNC-Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal.

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 (AβO), the species implicated in synaptic loss during the initial disease stages, induce endoplasmic reticulum (ER) stress in cultured neurons. Here, we investigated whether AβO trigger ER stress by an NMDAR-dependent mechanism leading to neuronal dysfunction and analyzed the contribution of GluN2A and GluN2B subunits of this glutamate receptor. Our data revealed that AβO 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 AβO induce NADPH oxidase (NOX)-mediated superoxide production downstream of GluN2B and impair ER and cytosolic Ca2+ homeostasis. These events precede changes in cell viability and activation of the ER stress-mediated apoptotic pathway, which was associated with translocation of the transcription factor GADD153/CHOP to the nucleus and occurred by a caspase-12-independent mechanism. Significantly, ER stress took place after AβO interaction with GluN2B subunits. In addition, AβO-induced ER stress and hippocampal dysfunction were prevented by ifenprodil, an antagonist of GluN2B subunits, while the GluN2A antagonist NVP-AAM077 only slightly attenuated AβO-induced neurotoxicity. Taken together, our results highlight the role of GluN2B subunit of NMDARs on ER stress-mediated hippocampal dysfunction caused by AβO suggesting that it might be a potential therapeutic target during the early stages of AD.

Key words: Alzheimer’s disease, amyloid pathology, amyloid-beta oligomers, neurodegenerative diseases, endoplasmic reticulum, N-methyl-D-aspartate receptors, GluN2B subunits, calcium homeostasis, NADPH oxidase

Link: http://www.ncbi.nlm.nih.gov/pubmed/22708890

Cláudia Pereira-png2

Proposed mechanisms for the N-methyl-D-aspartate receptor (NMDAR)-dependent endoplasmic reticulum (ER) stress induced by amyloid-beta oligomers (AβO) in mature hippocampal cells.

AβO can interact with or close to the GluN2B subunit of NMDAR (1), leading to the early rise of cytosolic Ca2+ levels (2). This increment activates NADPH oxidase (NOX) (3) and subsequently triggers the production of superoxide radicals (O2.-) (4), which in turn induces an ER stress response (5) characterized by accumulation of misfolded proteins in ER lumen (6) and ER Ca2+ depletion (7). In order to re-establish its normal functioning, cells activate ER stress sensors, including IRE1 and the downstream transcription factor XBP-1 (8) and up-regulate ER chaperones, such as GRP78 (9). However, when the AβO toxic insult is prolonged, an ER stress-mediated cell death pathway is induced increasing the levels of the pro-apoptotic transcription factor GADD153⁄CHOP in the nucleus where it triggers apoptosis (10).

 

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