title: EphA4 activation of c-Abl mediates synaptic loss and LTP blockade caused by amyloid-β oligomers.
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.
authors.affiliation: Departamento de Biología Celular y Molecular, Laboratorio de Señalización Celular, Facultad de Ciencias Biológicas, P. Universidad Católica de Chile, Santiago, Chile.
authors.forename: Lina M
authors.initials: LM
authors.lastname: Vargas
authors.affiliation: Departamento de Biología Celular y Molecular, Laboratorio de Señalización Celular, Facultad de Ciencias Biológicas, P. Universidad Católica de Chile, Santiago, Chile.
authors.forename: Nancy
authors.initials: N
authors.lastname: Leal
authors.affiliation: Departamento de Biología Celular y Molecular, Laboratorio de Señalización Celular, Facultad de Ciencias Biológicas, P. Universidad Católica de Chile, Santiago, Chile.
authors.forename: Lisbell D
authors.initials: LD
authors.lastname: Estrada
authors.affiliation: Departamento de Biología Celular y Molecular, Laboratorio de Señalización Celular, Facultad de Ciencias Biológicas, P. Universidad Católica de Chile, Santiago, Chile.
authors.forename: Adrian
authors.initials: A
authors.lastname: González
authors.affiliation: Departamento de Biología Celular y Molecular, Centro de Envejecimiento y Regeneración (CARE), Facultad de Ciencias Biológicas, P. Universidad Católica de Chile, Santiago, Chile.
authors.forename: Felipe
authors.initials: F
authors.lastname: Serrano
authors.affiliation: Departamento de Biología Celular y Molecular, Millenium Nucleus in Stress and Addiction, Facultad de Ciencias Biológicas, P. Universidad Católica de Chile, Santiago, Chile.
authors.forename: Katherine
authors.initials: K
authors.lastname: Araya
authors.affiliation: Departamento de Biología Celular y Molecular, Millenium Nucleus in Stress and Addiction, Facultad de Ciencias Biológicas, P. Universidad Católica de Chile, Santiago, Chile.
authors.forename: Katia
authors.initials: K
authors.lastname: Gysling
authors.affiliation: Departamento de Biología Celular y Molecular, Centro de Envejecimiento y Regeneración (CARE), Facultad de Ciencias Biológicas, P. Universidad Católica de Chile, Santiago, Chile.
authors.forename: Nibaldo C
authors.initials: NC
authors.lastname: Inestrosa
authors.affiliation: Sanford-Burnham Medical Research Institute, La Jolla, California, United States of America.
authors.forename: Elena B
authors.initials: EB
authors.lastname: Pasquale
authors.affiliation: Departamento de Biología Celular y Molecular, Laboratorio de Señalización Celular, Facultad de Ciencias Biológicas, P. Universidad Católica de Chile, Santiago, Chile.
authors.forename: Alejandra R
authors.initials: AR
authors.lastname: Alvarez
mesh_terms: D000544:Alzheimer Disease / Q000473:pathology / Q000503:physiopathology; D016229:Amyloid beta-Peptides / Q000494:pharmacology* / Q000502:physiology; D000818:Animals; D002478:Cells, Cultured; D049229:Dendritic Spines / Q000378:metabolism; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D017774:Long-Term Potentiation / Q000187:drug effects*; D018345:Mice, Knockout; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D010766:Phosphorylation; D016315:Proto-Oncogene Proteins c-abl / Q000378:metabolism*; D017207:Rats, Sprague-Dawley; D036122:Receptor, EphA4 / Q000378:metabolism*; D013569:Synapses / Q000473:pathology
chemical_list: D016229:Amyloid beta-Peptides; D036122:Receptor, EphA4; D016315:Proto-Oncogene Proteins c-abl