Antibody to the extracellular domain of the low affinity NGF receptor stimulates p75(NGFR)-mediated apoptosis in cultured sympathetic neurons.
Recent evidence has established a role for p75(NGFR) in developmentally regulated neuronal cell death. Although cell death due to NGF withdrawal is a well described, apoptosis in sympathetic neurons through stimulation of p75(NGFR) has not been clearly demonstrated. We have found that an antibody directed against the extracellular domain of murine p75(NGFR) profoundly effects the survival of short-term cultures of sympathetic neurons. Rat superior cervical ganglion neurons grown in the presence of NGF and treated with the bioactive antibody (9651) display a dose-dependent increase in cell death. This effect was independent of NGF concentration and partially reversed by either depolarizing stimuli or forskolin. The response to 9651 seems to act directly through a p75(NGFR)-mediated pathway and not by disturbing p75(NGFR)/TrkA interactions. Moreover, the kinetics of antibody stimulated cell death was more rapid than the cell death resulting from removal of NGF and treatment with CNTF failed to promote neuronal survival in the presence of 9651. Initiation of cell death is often associated with decreased NFkappaB activity, whereas survival or rescue correlates with increased NFkappaB. Increases in NFkappaB, however, have been observed in neurons in several diseases and late in apoptosis in differentiated PC12 cells. Time course studies revealed a rapid decrease in NFkappaB activity and a slight, but persistent increase in binding that correlated with decline in cell numbers 3 hr after treatment. These results suggest the cell death program is initiated shortly after antibody activation of p75(NGFR) and a subpopulation of cells may remain susceptible to rescue.
Freidin
M M
MM
Department of Neuroscience, Albert Einstein College of Medicine, Bronx, New York 10461, USA. mmfreidi@ix.netcom.com
D000818:Animals; D000831:Animals, Newborn; D000906:Antibodies / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D020932:Nerve Growth Factor / Q000494:pharmacology*; D051381:Rats; D020800:Receptor, Nerve Growth Factor / Q000187:drug effects* / Q000276:immunology / Q000502:physiology; D017783:Superior Cervical Ganglion / Q000187:drug effects* / Q000502:physiology; D013564:Sympathetic Nervous System / Q000166:cytology
D000906:Antibodies; D020800:Receptor, Nerve Growth Factor; D020932:Nerve Growth Factor