The role of p75NTR in inducing neuronal death and axonal degeneration after injury

MONTROULL, LAURA; ROTHBARD, D; ZANIN, JUAN PABLO; LEVISON, S; FRIEDMAN, WILMA J.

Congreso; Neurotrophic Factors, From Cellular Mechanisms to Function in Behavior and Disease; 2017

Factors that regulate neuronal survival or death, especially after injury, have a critical impact on neural function. Proneurotrophins are selective, high-affinity ligands for p75NTR with its co-receptor sortilin, and can activate p75NTR-mediated apoptosis. After damage in the adult brain, expression of p75NTR is induced in numerous CNS neurons and has been shown to regulate neuronal cell death in several injury models. We have previously demonstrated that p75NTR is induced after injury induced either by seizures or by contusion in a model of traumatic brain injury (TBI). Moreover, blocking either p75NTR or the proNGF ligand, can attenuate neuronal death. To test the hypothesis that p75NTR promotes secondary cell death, we provided a p75NTR siRNA intranasally immediately following a controlled cortical injury administered to adult C57/Bl6 mice. Data obtained are in agreement with previous findings that p75NTR KO mice demonstrated 2fold fewer apoptotic neurons 3 DPI. Furthermore, knockdown of p75NTR improved overall neurological function and in particular, improved sensorimotor performance on beam walking tests. Similar results were obtained when p75NTR ligands (proNGF and proBDNF) were blocked, suggesting an active role of this receptor and its ligands in inducing neuronal death after TBI. In addition to promoting neuronal apoptosis, we are also investigating a role for p75NTR in regulating axonal degeneration in a model of concussive brain injury and determining whether this is independent of neuronal death, or part of a continuum leading to neuronal death