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Amyloid beta peptide 1-42 disturbs intracellular calcium homeostasis through activation of GluN2B-containing N-methyl-D-aspartate receptors in cortical cultures

Ferreira, I.L. and Bajouco, L.M. and Oliveira, C.R. and Auberson, Yves and Rego, A.C. and Mota, S.I. (2011) Amyloid beta peptide 1-42 disturbs intracellular calcium homeostasis through activation of GluN2B-containing N-methyl-D-aspartate receptors in cortical cultures. Cell Calcium. ISSN 0143-4160

Abstract

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder that leads to debilitating cognitive deficits. Recent evidence demonstrates that glutamate receptors are dysregulated by amyloid beta peptide (Aβ) oligomers, resulting in disruption of glutamatergic synaptic transmission which parallels early cognitive deficits. Although it is well accepted that neuronal death in AD is related to disturbed Ca2+i homeostasis, little is known about the contribution of NMDARs containing NR2A or NR2B subunits on Aβ-induced Ca2+i rise and neuronal dysfunction. Thus, the main goal of this work was to evaluate the role of NMDAR subunits in dysregulation of Ca2+i homeostasis induced by Aβ 1-42 oligomers in rat cerebral cortical neurons. The involvement of NMDARs was evaluated by pharmacological inhibition with MK-801 or the selective NR2A and NR2B subunit antagonists NVP-AAM077 and ifenprodil, respectively. We show that Aβ oligomers, like NMDA, increase Ca2+i levels mainly through activation of NMDARs containing NR2B subunits. Conversely, NR2A-NMDARs antagonism potentiates Ca2+i rise induced by a high concentration of Aβ (1 µM), suggesting that NR2A and NR2B subunits have opposite roles in regulating Ca2+i homeostasis. Moreover, Aβ oligomers modulate NMDA-induced responses and vice-versa. Indeed, pre-exposure to Aβ (1 µM) decrease NMDA-evoked Ca2+I rise and pre-exposure to NMDA decrease Aβ response. Interestingly, simultaneous addition of Aβ and NMDA potentiate Ca2+I levels, being this effect appositively regulated by NR2A and NR2B subunits. This study contributes to the understanding of the molecular basis of early AD pathogenesis, evidencing the role of NR2A and NR2B subunits as selective molecular targets for therapeutic intervention in AD.

Item Type: Article
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Additional Information: author can archive post-print (ie final draft post-refereeing); Publisher's version/PDF cannot be used
Keywords: Alzheimer's disease, amyloid beta peptide (Aβ) oligomers, calcium, N-methyl-D-aspartate receptor, NR2A subunit, NR2B subunit
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Date Deposited: 13 Oct 2015 13:15
Last Modified: 13 Oct 2015 13:15
URI: https://oak.novartis.com/id/eprint/4473

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