期刊
PLOS ONE
卷 9, 期 3, 页码 -出版社
PUBLIC LIBRARY SCIENCE
DOI: 10.1371/journal.pone.0092309
关键词
-
资金
- FONDECYT [3120015, 1120512, 11130561]
- FONDEF [D10I1077]
- National Institutes of Health [CA138390, HD025938]
The early stages of Alzheimer's disease are characterised by impaired synaptic plasticity and synapse loss. Here, we show that amyloid-beta oligomers (A beta Os) activate the c-Abl kinase in dendritic spines of cultured hippocampal neurons and that c-Abl kinase activity is required for A beta Os-induced synaptic loss. We also show that the EphA4 receptor tyrosine kinase is upstream of c-Abl activation by A beta Os. EphA4 tyrosine phosphorylation (activation) is increased in cultured neurons and synaptoneurosomes exposed to A beta Os, and in Alzheimer-transgenic mice brain. We do not detect c-Abl activation in EphA4-knockout neurons exposed to A beta Os. More interestingly, we demonstrate EphA4/c-Abl activation is a key-signalling event that mediates the synaptic damage induced by A beta Os. 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 beta Os. Moreover, EphA4-/- neurons or sh-EphA4-transfected neurons showed reduced synaptotoxicity by A beta Os. Our results are consistent with EphA4 being a novel receptor that mediates synaptic damage induced by A beta Os. EphA4/c-Abl signalling could be a relevant pathway involved in the early cognitive decline observed in Alzheimer's disease patients.
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