P75 neurotrophin receptor signaling in nervous system injury and degeneration: paradox and opportunity

Department of Neuroscience, Karolinska Institute, 17177 Stockholm, Sweden.
Trends in Neurosciences (Impact Factor: 13.56). 04/2012; 35(7):431-40. DOI: 10.1016/j.tins.2012.03.007
Source: PubMed


Injury or insult to the adult nervous system often results in reactivation of signaling pathways that are normally only active during development. The p75 neurotrophin receptor (p75(NTR)) is one such signaling molecule whose expression increases markedly following neural injury in many of the same cell types that express p75(NTR) during development. A series of studies during the past decade has demonstrated that p75(NTR) signaling contributes to neuronal and glial cell damage, axonal degeneration and dysfunction during injury and cellular stress. Why the nervous system reacts to injury by inducing a molecule that aids the demise of cells and axons is a biological paradox that remains to be explained satisfactorily. On the other hand, it may offer unique therapeutic opportunities for limiting the severity of nervous system injury and disease.

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    • "p75NTR is abundantly expressed by these neurons in adulthood [2] and its signaling can positively or negatively affect the condition of BFCNs depending on the presence of several factors including co-receptors and ligands [3], [4]. For example, nerve growth factor (NGF) signaling through p75NTR may promote cell survival or death depending on the presence of its high-affinity receptor TrkA [3], [4]. Neuronal degeneration also occurs when amyloid-β (Aβ)1–40 binds to p75NTR [5], [6]. "
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    ABSTRACT: Degeneration of basal forebrain cholinergic neurons contributes significantly to the cognitive deficits associated with Alzheimer's disease (AD) and has been attributed to aberrant signaling through the neurotrophin receptor p75 (p75NTR). Thus, modulating p75NTR signaling is considered a promising therapeutic strategy for AD. Accordingly, our laboratory has developed small molecule p75NTR ligands that increase survival signaling and inhibit amyloid-β-induced degenerative signaling in in vitro studies. Previous work found that a lead p75NTR ligand, LM11A-31, prevents degeneration of cholinergic neurites when given to an AD mouse model in the early stages of disease pathology. To extend its potential clinical applications, we sought to determine whether LM11A-31 could reverse cholinergic neurite atrophy when treatment begins in AD mouse models having mid- to late stages of pathology. Reversing pathology may have particular clinical relevance as most AD studies involve patients that are at an advanced pathological stage. In this study, LM11A-31 (50 or 75 mg/kg) was administered orally to two AD mouse models, Thy-1 hAPPLond/Swe (APPL/S) and Tg2576, at age ranges during which marked AD-like pathology manifests. In mid-stage male APPL/S mice, LM11A-31 administered for 3 months starting at 6-8 months of age prevented and/or reversed atrophy of basal forebrain cholinergic neurites and cortical dystrophic neurites. Importantly, a 1 month LM11A-31 treatment given to male APPL/S mice (12-13 months old) with late-stage pathology reversed the degeneration of cholinergic neurites in basal forebrain, ameliorated cortical dystrophic neurites, and normalized increased basal forebrain levels of p75NTR. Similar results were seen in female Tg2576 mice. These findings suggest that LM11A-31 can reduce and/or reverse fundamental AD pathologies in late-stage AD mice. Thus, targeting p75NTR is a promising approach to reducing AD-related degenerative processes that have progressed beyond early stages.
    PLoS ONE 08/2014; 9(8):e102136. DOI:10.1371/journal.pone.0102136 · 3.23 Impact Factor
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    • "Since activated Muller cells and microglia can influence neurons and blood vessels through upregulation of p75NTR [29], [32], pro-neurotrophins [29], [33], cytokines [28], [33] and angiogenic factors [13], [34], we performed Western blots to examine the effects of EPO treatment on p75NTR, pro-NT3, TNFα, VEGF-A and PEDF expression (Figure 8). We found that EPO tended to reduce p75NTR (P = 0.22) and significantly decreased pro-NT3 (P = 0.02) expression but did not affect TNFα expression (Figure 8, A and B). "
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    ABSTRACT: Objective Royal College of Surgeons (RCS) rats develop vasculopathy as photoreceptors degenerate. The aim of this study was to examine the effect of erythropoietin (EPO) on retinopathy in RCS rats. Methods Fluorescein angiography was used to monitor retinal vascular changes over time. Changes in retinal glia and vasculature were studied by immunostaining. To study the effects of EPO on retinal pathology, EPO (5000 IU/kg) was injected intraperitoneally in 14 week old normal and RCS rats twice a week for 4 weeks. Changes in the retinal vasculature, glia and microglia, photoreceptor apoptosis, differential expression of p75 neurotrophin receptor (p75NTR), pro-neurotrophin 3 (pro-NT3), tumour necrosis factor-α (TNFα), pigment epithelium derived factor (PEDF) and vascular endothelial growth factor-A (VEGF-A), the production of CD34+ cells and mobilization of CD34+/VEGF-R2+ cells as well as recruitment of CD34+ cells into the retina were examined after EPO treatment. Results RCS rats developed progressive capillary dropout and subretinal neovascularization which were accompanied by retinal gliosis. Systemic administration of EPO stabilized the retinal vasculature and inhibited the development of focal vascular lesions. Further studies showed that EPO modulated retinal gliosis, attenuated photoreceptor apoptosis and p75NTR and pro-NT3 upregulation, promoted the infiltration of ramified microglia and stimulated VEGF-A expression but had little effect on TNFα and PEDF expression. EPO stimulated the production of red and white blood cells and CD34+ cells along with effective mobilization of CD34+/VEGF-R2+ cells. Immunofluorescence study demonstrated that EPO enhanced the recruitment of CD34+ cells into the retina. Conclusions Our results suggest that EPO has therapeutic potentials in treatment of neuronal and vascular pathology in retinal disease. The protective effects of EPO on photoreceptors and the retinal vasculature may involve multiple mechanisms including regulation of retinal glia and microglia, inhibition of p75NTR-pro-NT3 signaling together with stimulation of production and mobilization of bone marrow derived cells.
    PLoS ONE 08/2014; 9(8):e104759. DOI:10.1371/journal.pone.0104759 · 3.23 Impact Factor
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    • "In contrast to their mature counterparts , proNTs induce apoptosis, growth cone collapse, and facilitate synaptic retraction by a mechanism that requires p75 NTR but is independent of Trk receptors (Lee et al., 2001; Nykjaer et al., 2004; Rö sch et al., 2005; Woo et al., 2005; Yano et al., 2009). The capacity of proNTs to induce apoptosis is considered particularly important in conditions of acute and insidious neuronal and glial cell degeneration such as spinal cord and peripheral nerve injury, seizure, and aging (Arancio and Chao, 2007; Beattie et al., 2002; Ibá n ˜ ez and Simi, 2012; Nykjaer et al., 2005; Petratos et al., 2003). "
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    ABSTRACT: Balancing trophic and apoptotic cues is critical for development and regeneration of neuronal circuits. Here we identify SorCS2 as a proneurotrophin (proNT) receptor, mediating both trophic and apoptotic signals in conjunction with p75(NTR). CNS neurons, but not glia, express SorCS2 as a single-chain protein that is essential for proBDNF-induced growth cone collapse in developing dopaminergic processes. SorCS2- or p75(NTR)-deficient in mice caused reduced dopamine levels and metabolism and dopaminergic hyperinnervation of the frontal cortex. Accordingly, both knockout models displayed a paradoxical behavioral response to amphetamine reminiscent of ADHD. Contrary, in PNS glia, but not in neurons, proteolytic processing produced a two-chain SorCS2 isoform that mediated proNT-dependent Schwann cell apoptosis. Sciatic nerve injury triggered generation of two-chain SorCS2 in p75(NTR)-positive dying Schwann cells, with apoptosis being profoundly attenuated in Sorcs2(-/-) mice. In conclusion, we have demonstrated that two-chain processing of SorCS2 enables neurons and glia to respond differently to proneurotrophins.
    Neuron 06/2014; 82(5):1074-1087. DOI:10.1016/j.neuron.2014.04.022 · 15.05 Impact Factor
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