| First Author | Vargas LM | Year | 2014 |
| Journal | PLoS One | Volume | 9 |
| Issue | 3 | Pages | e92309 |
| PubMed ID | 24658113 | Mgi Jnum | J:214156 |
| Mgi Id | MGI:5588508 | Doi | 10.1371/journal.pone.0092309 |
| Citation | Vargas LM, et al. (2014) EphA4 activation of c-Abl mediates synaptic loss and LTP blockade caused by amyloid-beta oligomers. PLoS One 9(3):e92309 |
| abstractText | The early stages of Alzheimer's disease are characterised by impaired synaptic plasticity and synapse loss. Here, we show that amyloid-beta oligomers (AbetaOs) activate the c-Abl kinase in dendritic spines of cultured hippocampal neurons and that c-Abl kinase activity is required for AbetaOs-induced synaptic loss. We also show that the EphA4 receptor tyrosine kinase is upstream of c-Abl activation by AbetaOs. EphA4 tyrosine phosphorylation (activation) is increased in cultured neurons and synaptoneurosomes exposed to AbetaOs, and in Alzheimer-transgenic mice brain. We do not detect c-Abl activation in EphA4-knockout neurons exposed to AbetaOs. More interestingly, we demonstrate EphA4/c-Abl activation is a key-signalling event that mediates the synaptic damage induced by AbetaOs. 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 AbetaOs. Moreover, EphA4-/- neurons or sh-EphA4-transfected neurons showed reduced synaptotoxicity by AbetaOs. Our results are consistent with EphA4 being a novel receptor that mediates synaptic damage induced by AbetaOs. EphA4/c-Abl signalling could be a relevant pathway involved in the early cognitive decline observed in Alzheimer's disease patients. |
