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PLoS One. 2014 Mar 21;9(3):e92309. doi: 10.1371/journal.pone.0092309. eCollection 2014.

EphA4 activation of c-Abl mediates synaptic loss and LTP blockade caused by amyloid-β oligomers.

Author information

1
Departamento de Biología Celular y Molecular, Laboratorio de Señalización Celular, Facultad de Ciencias Biológicas, P. Universidad Católica de Chile, Santiago, Chile.
2
Departamento de Biología Celular y Molecular, Centro de Envejecimiento y Regeneración (CARE), Facultad de Ciencias Biológicas, P. Universidad Católica de Chile, Santiago, Chile.
3
Departamento de Biología Celular y Molecular, Millenium Nucleus in Stress and Addiction, Facultad de Ciencias Biológicas, P. Universidad Católica de Chile, Santiago, Chile.
4
Sanford-Burnham Medical Research Institute, La Jolla, California, United States of America.

Abstract

The early stages of Alzheimer's disease are characterised by impaired synaptic plasticity and synapse loss. Here, we show that amyloid-β oligomers (AβOs) activate the c-Abl kinase in dendritic spines of cultured hippocampal neurons and that c-Abl kinase activity is required for AβOs-induced synaptic loss. We also show that the EphA4 receptor tyrosine kinase is upstream of c-Abl activation by AβOs. EphA4 tyrosine phosphorylation (activation) is increased in cultured neurons and synaptoneurosomes exposed to AβOs, and in Alzheimer-transgenic mice brain. We do not detect c-Abl activation in EphA4-knockout neurons exposed to AβOs. More interestingly, we demonstrate EphA4/c-Abl activation is a key-signalling event that mediates the synaptic damage induced by AβOs. 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 AβOs. Moreover, EphA4-/- neurons or sh-EphA4-transfected neurons showed reduced synaptotoxicity by AβOs. Our results are consistent with EphA4 being a novel receptor that mediates synaptic damage induced by AβOs. EphA4/c-Abl signalling could be a relevant pathway involved in the early cognitive decline observed in Alzheimer's disease patients.

PMID:
24658113
PMCID:
PMC3962387
DOI:
10.1371/journal.pone.0092309
[Indexed for MEDLINE]
Free PMC Article
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