RGD Reference Report - EphA4 activation of c-Abl mediates synaptic loss and LTP blockade caused by amyloid-ß oligomers. - Rat Genome Database

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

Authors: Vargas, Lina M  Leal, Nancy  Estrada, Lisbell D  González, Adrian  Serrano, Felipe  Araya, Katherine  Gysling, Katia  Inestrosa, Nibaldo C  Pasquale, Elena B  Alvarez, Alejandra R 
Citation: Vargas LM, etal., PLoS One. 2014 Mar 21;9(3):e92309. doi: 10.1371/journal.pone.0092309. eCollection 2014.
RGD ID: 12911004
Pubmed: PMID:24658113   (View Abstract at PubMed)
PMCID: PMC3962387   (View Article at PubMed Central)
DOI: DOI:10.1371/journal.pone.0092309   (Journal Full-text)

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



Gene Ontology Annotations    Click to see Annotation Detail View

Biological Process

  
Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
Epha4Ratephrin receptor signaling pathway involved_inIGIComplexPortal:CPX-1134PMID:24658113ARUK-UCL 
Abl1Ratregulation of modification of synaptic structure involved_inIGIComplexPortal:CPX-1134PMID:24658113ARUK-UCL 
Epha4Ratregulation of modification of synaptic structure involved_inIGIComplexPortal:CPX-1134PMID:24658113ARUK-UCL 

Cellular Component

  
Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
Abl1Ratdendrite located_inIDA PMID:24658113ARUK-UCL 
Epha4Ratdendritic shaft located_inIDA PMID:24658113ARUK-UCL 
Epha4Ratdendritic spine located_inIDA PMID:24658113ARUK-UCL 
Abl1Ratneuronal cell body located_inIDA PMID:24658113ARUK-UCL 
Abl1Ratnucleus located_inIDA PMID:24658113ARUK-UCL 

Molecular Function

  
Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
Epha4Ratprotein binding enablesIPIUniProtKB:P00520PMID:24658113ARUK-UCL 

Objects Annotated

Genes (Rattus norvegicus)
Abl1  (ABL proto-oncogene 1, non-receptor tyrosine kinase)
Epha4  (Eph receptor A4)


Additional Information