%0 Journal Article
%T EphA4 Activation of c-Abl Mediates Synaptic Loss and LTP Blockade Caused by Amyloid-¦Â Oligomers
%A Lina M. Vargas
%A Nancy Leal
%A Lisbell D. Estrada
%A Adrian Gonz¨¢lez
%A Felipe Serrano
%A Katherine Araya
%A Katia Gysling
%A Nibaldo C. Inestrosa
%A Elena B. Pasquale
%A Alejandra R. Alvarez
%J PLOS ONE
%D 2014
%I Public Library of Science (PLoS)
%R 10.1371/journal.pone.0092309
%X The early stages of Alzheimer's disease are characterised by impaired synaptic plasticity and synapse loss. Here, we show that amyloid-¦Â oligomers (A¦ÂOs) activate the c-Abl kinase in dendritic spines of cultured hippocampal neurons and that c-Abl kinase activity is required for A¦ÂOs-induced synaptic loss. We also show that the EphA4 receptor tyrosine kinase is upstream of c-Abl activation by A¦ÂOs. EphA4 tyrosine phosphorylation (activation) is increased in cultured neurons and synaptoneurosomes exposed to A¦ÂOs, and in Alzheimer-transgenic mice brain. We do not detect c-Abl activation in EphA4-knockout neurons exposed to A¦ÂOs. More interestingly, we demonstrate EphA4/c-Abl activation is a key-signalling event that mediates the synaptic damage induced by A¦ÂOs. According to this results, the EphA4 antagonistic peptide KYL and c-Abl inhibitor STI prevented i) dendritic spine reduction, ii) the blocking of LTP induction and iii) neuronal apoptosis caused by A¦ÂOs. Moreover, EphA4-/- neurons or sh-EphA4-transfected neurons showed reduced synaptotoxicity by A¦ÂOs. Our results are consistent with EphA4 being a novel receptor that mediates synaptic damage induced by A¦ÂOs. EphA4/c-Abl signalling could be a relevant pathway involved in the early cognitive decline observed in Alzheimer's disease patients.
%U http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0092309