NGF acts via p75 low‐affinity neurotrophin receptor and calpain inhibition to reduce UV neurotoxicity

Abstract

The relative roles of the high-affinity nerve growth factor (NGF) receptor, TrkA, and low-affinity p75 neurotrophin receptor (p75NTR) in neuronal survival are an active research area. We reported previously that UV treatment induces a calpain-dependent, delayed neuronal death. We show here that NGF inhibits this UV-induced cortical neuron death. Interestingly, NGF neuroprotection requires p75NTR. Because it has been reported that NGF binding to p75NTR leads to ceramide generation, we evaluated whether ceramide was also neuroprotective. We found that ceramide also inhibits UV toxicity, and that the actions of ceramide and NGF were not additive. Moreover, cycloheximide inhibited ceramide and NGF neuroprotection, suggesting that their actions require new protein synthesis. Consistent with this possibility, we found that NGF activates the expression of genes such as calbindin. Lastly, we explored the role of calpain in NGF actions. NGF and ceramide both reduced the level of calpain activation after UV treatment. This NGF effect was p75NTR dependent. Overall, we interpret these results as consistent with an NGF neuroprotective pathway wherein p75NTR activation leads sequentially to ceramide generation, new protein synthesis, and inhibition of calpain activation. Overall, these results provide insight into a p75NTR dependent pathway of NGF neuroprotection.

Adipose-derived Stem Cell Conditioned Media Extends Survival time of a mouse model of Amyotrophic Lateral Sclerosis

“…Growing evidence has shown that NGF induces neuronal survival with low-affinity binding to the p75 neurotrophin receptor (p75NTR) 54 . Additionally, it was shown that NGF-induced neuroprotection against OGD insult by inhibiting OGD-induced p38 activation 55 and against UV neurotoxicity by inhibiting calpain activity 56 . Furthermore, increased production of NGF in central nervous system (CNS) during diseases is able to suppress inflammation by switching the immune response to an anti-inflammatory 57 .…”

Nerve growth factor affects Ca2+ currents via the p75 receptor to enhance prolactin mRNA levels in GH3 rat pituitary cells

“…MC192 has been used with this same purpose in several previous studies (e.g. Bui et al 2002; Numakawa et al 2003; McCollum & Estus, 2004). Figure 10 and shows that MC192 fully blocked the enhancement of HVA Ca 2+ current produced by a 60‐min exposure to NGF.…”

“…At variance with this, our data indicate that the effects of NGF on Ca 2+ currents in GH 3 cells are mediated by p75 in a TrkA‐independent way. Neither the early increase in the L‐type current nor the late increase in the T‐type current could be observed when NGF was applied in combination with MC192, an anti‐p75 antibody that has proved to be a valuable tool to identify p75‐mediated responses in rat neurons (Blochl & Sirrenberg, 1996; Numakawa et al 2003; McCollum & Estus, 2004) and PC12 cells (Bui et al 2002). By contrast, both increases persisted in the presence of K252a, a potent inhibitor of the tyrosine kinase activity of Trk receptors (Berg et al 1992).…”

Small-molecule modulation of the p75 neurotrophin receptor inhibits a wide range of tau molecular pathologies and their sequelae in P301S tauopathy mice

“…Evidence suggests that calpains can promote tau fragmentation in AD and other disease contexts [25] and p75 NTR signaling can regulate calpain activity [50]. Activation of calpains results in cleavage of the 250 kDa cytoskeletal protein α-fodrin to fragments of ~ 145 kDa, and the ratio of the cleaved fragments to actin serves as a measure of calpain activity.…”