N-Methyl-d-aspartate receptors are required for synaptic targeting of Alzheimer’s toxic amyloid-β peptide oligomers
Article first published online: 11 NOV 2010
© 2010 The Authors. Journal of Neurochemistry © 2010 International Society for Neurochemistry
Journal of Neurochemistry
Volume 115, Issue 6, pages 1520–1529, December 2010
How to Cite
Decker, H., Jürgensen, S., Adrover, M. F., Brito-Moreira, J., Bomfim, T. R., Klein, W. L., Epstein, A. L., De Felice, F. G., Jerusalinsky, D. and Ferreira, S. T. (2010), N-Methyl-d-aspartate receptors are required for synaptic targeting of Alzheimer’s toxic amyloid-β peptide oligomers. Journal of Neurochemistry, 115: 1520–1529. doi: 10.1111/j.1471-4159.2010.07058.x
- Issue published online: 1 DEC 2010
- Article first published online: 11 NOV 2010
- Accepted manuscript online: 15 OCT 2010 12:55PM EST
- Received July13, 2010; revised manuscript received October 1, 2010; accepted October 4, 2010.
- Aβ oligomers;
- Alzheimer’s disease;
- NMDA receptor;
- synapse dysfunction
J. Neurochem. (2010) 115, 1520–1529.
Soluble amyloid-β peptide (Aβ) oligomers, known to accumulate in Alzheimer’s disease brains, target excitatory post-synaptic terminals. This is thought to trigger synapse deterioration, a mechanism possibly underlying memory loss in early stage Alzheimer’s disease. A major unknown is the identity of the receptor(s) targeted by oligomers at synapses. Because oligomers have been shown to interfere with N-methyl-d-aspartate receptor (NMDAR) function and trafficking, we hypothesized that NMDARs might be required for oligomer binding to synapses. An amplicon vector was used to knock-down NMDARs in mature hippocampal neurons in culture, yielding 90% reduction in dendritic NMDAR expression and blocking neuronal oxidative stress induced by Aβ oligomers, a pathological response that has been shown to be mediated by NMDARs. Remarkably, NMDAR knock-down abolished oligomer binding to dendrites, indicating that NMDARs are required for synaptic targeting of oligomers. Nevertheless, oligomers do not appear to bind directly to NMDARs as indicated by the fact that both oligomer-attacked and non-attacked neurons exhibit similar surface levels of NMDARs. Furthermore, pre-treatment of neurons with insulin down-regulates oligomer-binding sites in the absence of a parallel reduction in surface levels of NMDARs. Establishing that NMDARs are key components of the synaptic oligomer binding complex may illuminate the development of novel approaches to prevent synapse failure triggered by Aβ oligomers.