Journal
CELL CALCIUM
Volume 49, Issue 3, Pages 184-190Publisher
ELSEVIER SCI LTD
DOI: 10.1016/j.ceca.2011.02.001
Keywords
Amyloid beta; NMDA receptors; Xenopus oocytes; Neuron death; Alzheimeris disease
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Funding
- CIBERNED
- Ministerio de Educacion y Ciencia [SAF2007/62380, SAF2008/732]
- La Marato de [TV3 063033]
- Gobierno Vasco
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Amyloid beta (A beta) oligomers accumulate in the brain tissue of Alzheimer disease patients and are related to disease pathogenesis. The precise mechanisms by which A beta oligomers cause neurotoxicity remain unknown. We recently reported that A beta oligomers cause intracellular Ca2+ overload and neuronal death that can be prevented by NMDA receptor antagonists. This study investigated whether A beta oligomers directly activated NMDA receptors (NMDARs) using NR1/NR2A and NR1/NR2B receptors that were heterologously expressed in Xenopus laevis oocytes. Indeed. A beta oligomers induced inward non-desensitizing currents that were blocked in the presence of the NMDA receptor antagonists memantine, APV, and MK-801. Intriguingly, the amplitude of the responses to A beta oligomers was greater for NR1/NR2A heteromers than for NR1/NR2B heteromers expressed in oocytes. Consistent with these findings, we observed that the increase in the cytosolic concentration of Ca2+ induced by A beta oligomers in cortical neurons is prevented by AP5, a broad spectrum NMDA receptor antagonist, but slightly attenuated by ifenprodil which blocks receptors with the NR2B subunit. Together, these results indicate that A beta oligomers directly activate NMDA receptors, particularly those with the NR2A subunit, and further suggest that drugs that attenuate the activity of such receptors may prevent A beta damage to neurons in Alzheimeris disease. (c) 2011 Elsevier Ltd. All rights reserved.
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