Activation of the neuronal c-Abl tyrosine kinase by amyloid-beta-peptide and reactive oxygen species.
The deposition and accumulation of amyloid-beta-peptide (Abeta) in the brain are considered a sine qua non for Alzheimer's disease. The experimental delivery of fibrilized Abeta serves as a cellular model for several facets of the disease including the induction of synaptic dysfunction and apoptosis. c-Abl kinase is involved in the regulation of apoptosis and its pro-apoptotic function is in part mediated by its interaction with p73, a p53 homologue. We found that c-Abl activation is involved in cell signals that regulate neuronal death response to Abeta fibrils. Abeta peptide fibrils induced an increase of the c-Abl activity in rat hippocampal neurons as well as an increase in nuclear p73 protein levels and the p73-c-Abl complex. The neuronal cell death induced by Abeta fibrils was prevented by the inhibition of c-Abl with imatinib mesylate (Gleevec or STI571) and by the inhibition c-Abl expression by RNAi. These results directly point to a therapeutic strategy for the treatment of Alzheimer's disease.
FONDAP Center for Cell and Molecular Biology Joaquin V. Luco, P. Universidad Católica de Chile, Santiago, 114-D, Chile. aalvarez@bio.puc.cl
Alejandra R
AR
Alvarez
Pablo C
PC
Sandoval
Nancy R
NR
Leal
Paula U
PU
Castro
Kenneth S
KS
Kosik
D000682:Amyloid / Q000494:pharmacology; D016229:Amyloid beta-Peptides / Q000502:physiology*; D000818:Animals; D017209:Apoptosis / Q000502:physiology; D016923:Cell Death; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000502:physiology; D004622:Embryo, Mammalian; D004789:Enzyme Activation; D016147:Genes, Tumor Suppressor; D006624:Hippocampus / Q000166:cytology / Q000201:enzymology* / Q000378:metabolism; D009474:Neurons / Q000201:enzymology* / Q000378:metabolism; D009687:Nuclear Proteins / Q000502:physiology; D018384:Oxidative Stress / Q000502:physiology; D016315:Proto-Oncogene Proteins c-abl / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism*; D000072160:Tumor Protein p73; D025521:Tumor Suppressor Proteins; D015854:Up-Regulation
D000682:Amyloid; D016229:Amyloid beta-Peptides; D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D017382:Reactive Oxygen Species; D000072160:Tumor Protein p73; D025521:Tumor Suppressor Proteins; D016315:Proto-Oncogene Proteins c-abl