Mechanisms of p75-mediated death of hippocampal neurons. Role of caspases.
Neurotrophins support neuronal survival and differentiation via Trk receptors, yet can also induce cell death via the p75 receptor. In these studies, we investigated signaling mechanisms governing p75-mediated death of hippocampal neurons, specifically the role of caspases. Although p75 is structurally a member of the Fas/TNFR1 receptor family, caspase-8 was not required for p75-mediated death, unlike other members of this receptor family. In contrast, p75-mediated neuronal death was associated with mitochondrial loss of cytochrome c and required Apaf-1 and caspase-9, -6, and -3. In particular, caspase-6 plays a central role in mediating neurotrophin-induced death, illuminating a novel role for this caspase. Inhibition of DIABLO/Smac, which blocks inhibitor of apoptosis proteins, protected cells from death, whereas simultaneous inhibition of both DIABLO/Smac and MIAP3 allowed trophin-induced death to proceed. In vivo, pilocarpine-induced seizures, previously shown to up-regulate p75 expression and increase neurotrophin production, caused activation of caspase-6 and -3 and cleavage of poly(ADP-ribose) polymerase in p75-expressing hippocampal neurons. In p75(-/-) mice, no activated caspase-3 was detected, and there was a marked reduction in the number of dying neurons after pilocarpine treatment compared with wild type mice. Neurotrophin-induced p75-mediated death is likely to play an important role in mediating neuronal loss consequent to brain injury.
Troy
Carol M
CM
Department of Pathology, Taub Institute for the Study of Alzheimer's Disease and the Aging Brain, Center for Neurobiology and Behavior, Columbia University College of Physicians and Surgeons, New York, NY 10032, USA.
Friedman
Jonathan E
JE
Friedman
Wilma J
WJ
D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000494:pharmacology; D020169:Caspases / Q000502:physiology*; D016923:Cell Death; D006624:Hippocampus / Q000473:pathology*; D008297:Male; D020932:Nerve Growth Factor / Q000494:pharmacology; D009474:Neurons / Q000473:pathology*; D051381:Rats; D017208:Rats, Wistar; D020800:Receptor, Nerve Growth Factor / Q000502:physiology*
D019208:Brain-Derived Neurotrophic Factor; D020800:Receptor, Nerve Growth Factor; D020932:Nerve Growth Factor; D020169:Caspases