Aβ oligomers induce glutamate release from hippocampal neurons.
Soluble oligomers of the amyloid-β peptide (AβOs) accumulate in Alzheimer's 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 Ca(2+) from the extracellular medium, indicating dependence on excitatory neuronal activity. AβOs enhanced both the release of pre-synaptic vesicles labeled by FM1-43 and 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 AbOs on glutamate dyshomeostasis. Results reveal a novel mechanism by which Ab oligomers promote abnormal release of glutamate in hippocampal neurons, which may contribute to dysregulation of excitatory signaling in the brain.
Institute of Medical Biochemistry, Federal University of Rio de Janeiro, Rio de Janeiro, RJ 21944-590, Brazil.
J
J
Brito-Moreira
A C
AC
Paula-Lima
T R
TR
Bomfim
F B
FB
Oliveira
F J
FJ
Sepúlveda
F G
FG
De Mello
L G
LG
Aguayo
R
R
Panizzutti
S T
ST
Ferreira
D016229:Amyloid beta-Peptides / Q000633:toxicity*; D000818:Animals; D002851:Chromatography, High Pressure Liquid; D018698:Glutamic Acid / Q000378:metabolism*; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D007150:Immunohistochemistry; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism*; D018408:Patch-Clamp Techniques; D051381:Rats; D017207:Rats, Sprague-Dawley
D016229:Amyloid beta-Peptides; D018698:Glutamic Acid