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

PloS one | Mar 24, 2014

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.

Pubmed ID: 24658113 RIS Download

Mesh terms: Alzheimer Disease | Amyloid beta-Peptides | Animals | Cells, Cultured | Dendritic Spines | Hippocampus | Humans | Long-Term Potentiation | Mice, Knockout | Neurons | Phosphorylation | Proto-Oncogene Proteins c-abl | Rats, Sprague-Dawley | Receptor, EphA4 | Synapses

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Associated grants

  • Agency: NCI NIH HHS, Id: P01 CA138390
  • Agency: NICHD NIH HHS, Id: P01 HD025938
  • Agency: NCI NIH HHS, Id: CA138390
  • Agency: NICHD NIH HHS, Id: HD025938

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Software suite for electrophysiology data acquisition and analysis by Molecular Devices. Used for the control and recording of voltage clamp, current clamp, and patch clamp experiments. The software suite consists of Clampex 11 Software for data acquisition, AxoScope 11 Software for background recording, Clampfit 11 Software for data analysis, and optional Clampfit Advanced Analysis Module for sophisticated and streamlined analysis.

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