Aβ Oligomers Induce Glutamate Release from Hippocampal Neurons

Soluble oligomers of the amyloid-beta peptide (A beta Os) accumulate in Alzheimer's disease (AD) brain and have been implicated in mechanisms of pathogenesis. The neurotoxicity of A beta Os appears to be, at least in part, due to dysregulation of glutamate signaling. Here, we show that A beta Os 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 A beta Os 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. A beta Os 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 GABA(A) receptors by taurine blocked the increase in extracellular glutamate levels, suggesting that selective pharmacological inhibition of neuronal activity can counteract the impact of A beta Os on glutamate dyshomeostasis. Results reveal a novel mechanism by which A beta oligomers promote abnormal release of glutamate from hippocampal neurons, which may contribute to dysregulation of excitatory signaling in the brain.