The p75 Neurotrophin Receptor Mediates Neuronal Apoptosis and Is Essential for Naturally Occurring Sympathetic Neuron Death

Abstract

Abstract. To determine whether the p75 neurotrophin receptor (p75NTR) plays a role in naturally occurring neuronal death, we examined neonatal sympathetic neurons that express both the TrkA tyrosine kinase receptor and p75NTR. When sympathetic neuron survival is maintained with low quantities of NGF or KCl, the neurotrophin brain-derived neurotrophic factor (BDNF), which does not activate Trk receptors on sympathetic neurons, causes neuronal apoptosis and increased phosphorylation of c-jun. Function-blocking antibody studies indicate that this apoptosis is due to BDNF-mediated activation of p75NTR. To determine the physiological relevance of these culture findings, we examined sympathetic neurons in BDNF Ϫ / Ϫ and p75NTR Ϫ / Ϫ mice. In BDNF Ϫ / Ϫ mice, sympathetic neuron number is increased relative to BDNF ϩ / ϩ littermates, and in p75NTR Ϫ / Ϫ mice, the normal period of sympathetic neuron death does not occur, with neuronal attrition occurring later in life. This deficit in apoptosis is intrinsic to sympathetic neurons, since cultured p75NTR Ϫ / Ϫ neurons die more slowly than do their wild-type counterparts. Together, these data indicate that p75NTR can signal to mediate apoptosis, and that this mechanism is essential for naturally occurring sympathetic neuron death.

A Novel p75NTR Signaling Pathway Promotes Survival, Not Death, of Immunopurified Neocortical Subplate Neurons

“…Importantly, NGF does not cause significant cell death, despite the fact that subplate neurons do not express the Trk receptor for NGF, TrkA. These observations differ significantly from results in sympathetic neurons and oligodendrocytes, in which p75NTR signaling promotes cell death in the absence of activated TrkA receptors (Bamji et al, 1998;Yoon et al, 1998). Coaddition of saturating amounts of both BDNF and NT3 does not increase subplate neuron survival above that with either factor alone (Fig.…”

“…Studies of mice carrying a gene deletion of p75NTR reveal that it is necessary for survival of sensory and basal forebrain cholinergic neurons, although, conversely, it is necessary for naturally occurring cell death in sympathetic, motor, and retinal neurons (Lee et al, 1992;Bamji et al, 1998;Brennan et al, 1999;Frade and Barde, 1999;Peterson et al, 1999). However, because both neuronal and non-neuronal cells express p75NTR, it is unclear from these studies, as well as studies of unpurified neurons in vitro, whether or not p75NTR functions in a cellautonomous manner for all of these neuronal populations.…”

“…In contrast, the role of p75NTR in neuronal survival is cell-type dependent. From studies of knock-out mice, p75NTR is known to be required for survival of nociceptive sensory neurons, although it mediates naturally occurring cell death of sympathetic and certain motor neurons (Lee et al, 1992;Bamji et al, 1998;Brennan et al, 1999;Frade and Barde, 1999). In vitro, p75NTR has been found to mediate neuronal survival by facilitating Trk signaling at low neurotrophin concentrations (Davies et al, 1993;Lee et al, 1994).…”

Selectivity of Cell Signaling in the Neuronal Response Based on NGF Mutations and Peptidomimetics in the Treatment of Alzheimers Disease

“…The co-presence of Trk on a neuron silences pro-apoptotic pathways by activation of the pro-survival transcription factor, NF-κB, which subsequently activates Akt (Bibel & Barde, 2000;Kaplan & Miller, 2000;Khursigara et al, 1999). Sympathetic neurons and basal forebrain neurons that were p75-deficient in p75-/-mice underwent robust axonal sprouting, hypertrophy, or target innervation with naturally-occurring developmental apoptosis being significantly delayed (Kaplan & Miller, 2000;Walsh et al, 1999;Yeo et al, 1997;Bamji et al, 1998). Without intrinsic catalytic activity, the p75 ICD appears to rely on docking of adaptor www.intechopen.com Aloyz et al, 1998;Salehi, et al, 2002;Muller, et al, 1998;de Chaves et al, 1997;Casademunt, et al, 1999;2 Chittka & Chao, 1999;3 Domeniconi et al, 2005;4 Khursigara et al, 1999;5 Susen, et al, 1999;Lad & Neet, 2003.…”

Nerve growth factor neuroprotection of ethanol-induced neuronal death in rat cerebral cortex is age dependent

“…The role of p75 during development is time-and area-dependent. For example, p75 can mediate cell death in specific populations, including oligodendrocytes and sympathetic neurons (e.g., Casaccia-Bonnefil et al, 1996;Bamji et al, 1998). In other models, e.g., cultured hippocampal neurons or PC12 cells, p75 mediates survival (Roux et al, 2001;Bui et al, 2002;Culmsee et al, 2002).…”