Tyrosine kinase nerve growth factor receptor switches from prosurvival to proapoptotic activity via Abeta-mediated phosphorylation.
The present study shows that increased Abeta production in hippocampal neurons, due to a failure of NGF signal, induces an unexpected phosphorylation of tyrosine kinase receptor A (TrkA), followed by activation of the phospholipase C gamma (PLCgamma) pathway and neuronal death. Such phosphorylation seems causally connected with 2 kinases known be involved in amyloidogenesis, Src and CDK5, and associated with alpha and gamma secretase-mediated p75 processing. Pharmacologic inhibition of TrkA phosphorylation and partial silencing of TrkA and/or p75 receptors prevent PLCgamma activation and protect neurons from death. Concomitantly with these events, TrkA, p75, Abeta peptides, and PS1 protein coimmunoprecipitate, suggesting their direct interplay in the subsequent onset of apoptotic death. Together, these findings depict a cellular mechanism whereby the same cellular transducing system may invert its intracellular message from trophic and antiapoptotic to a death signaling, which could also have relevance in the onset of Alzheimer's disease.
Matrone
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C
Institute of Neurobiology and Molecular Medicine, National Research Council, via del Fosso del Fiorano 64, 00143 Rome, Italy. c.matrone@inmm.cnr.it
Marolda
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Ciafrè
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Ciotti
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MT
Mercanti
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Calissano
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D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D002467:Cell Nucleus / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D051360:Cyclin-Dependent Kinase 5 / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D020868:Gene Silencing / Q000187:drug effects; D006624:Hippocampus / Q000166:cytology; D047468:Immunoprecipitation; D020932:Nerve Growth Factor / Q000494:pharmacology; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000201:enzymology; D051966:Phospholipase C gamma / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D053764:Presenilin-1 / Q000737:chemistry; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D020917:Receptor, trkA / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors; D019061:src-Family Kinases / Q000378:metabolism
D016229:Amyloid beta-Peptides; D053764:Presenilin-1; D020932:Nerve Growth Factor; D020917:Receptor, trkA; D019061:src-Family Kinases; D051360:Cyclin-Dependent Kinase 5; D051057:Proto-Oncogene Proteins c-akt; D051966:Phospholipase C gamma