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Aβ Oligomers Induce Glutamate Release from Hippocampal Neurons

[ Vol. 8 , Issue. 5 ]

Author(s):

J. Brito-Moreira, A. C. Paula-Lima, T. R. Bomfim, F. F. Oliveira, F. J. Sepulveda, F. G. De Mello, L. G. Aguayo, R. Panizzutti and S. T. Ferreira   Pages 552 - 562 ( 11 )

Abstract:


Soluble oligomers of the amyloid-β peptide (AβOs) accumulate in Alzheimers disease (AD) brain and have been implicated in mechanisms of pathogenesis. The neurotoxicity of AβOs appears to be, at least in part, due to dysregulation of glutamate signaling. Here, we show that AβOs promote extracellular accumulation of glutamate and D-serine, a co-agonist at glutamate receptors of the N-methyl-D-aspartate subtype (NMDARs), in hippocampal neuronal cultures. The increase in extracellular glutamate levels induced by AβOs was blocked by the sodium channel blocker tetrodotoxin (TTX), by the NMDAR blocker (+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine maleate (MK-801) and by removal of Ca2+ from the extracellular medium, indicating dependence on excitatory neuronal activity. AβOs enhanced the release of pre-synaptic vesicles labeled by FM1-43 as well as spontaneous post-synaptic activity measured by whole-cell patch-clamp. Activation of inhibitory GABAA receptors by taurine blocked the increase in extracellular glutamate levels, suggesting that selective pharmacological inhibition of neuronal activity can counteract the impact of AβOs on glutamate dyshomeostasis. Results reveal a novel mechanism by which Aβ oligomers promote abnormal release of glutamate from hippocampal neurons, which may contribute to dysregulation of excitatory signaling in the brain.

Keywords:

Aβ oligomers, Alzheimer's disease, D-serine, glutamate, taurine, Aβoligomers, excitatory synapses, Hippocampal Slices, glial cells

Affiliation:

Institute of Medical Biochemistry and Program in Basic and Clinical Neuroscience, Institute of Biomedical Sciences, Federal University of Rio de Janeiro, Rio de Janeiro, RJ 21944-590, Brazil.



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