Evidence of p75 Neurotrophin Receptor Involvement in the Central Nervous System Pathogenesis of Classical Scrapie in Sheep and a Transgenic Mouse Model.

Tomás Barrio,Martí Pumarola,Marina Betancor,Alicia Otero,Eva Monleón,Marta Monzón,Juan José Badiola,Enric Vidal,Rosa Bolea,Inmaculada Martín-Burriel

doi:10.3390/ijms22052714

Abstract

Neurotrophins constitute a group of growth factor that exerts important functions in the nervous system of vertebrates. They act through two classes of transmembrane receptors: tyrosine-kinase receptors and the p75 neurotrophin receptor (p75NTR). The activation of p75NTR can favor cell survival or apoptosis depending on diverse factors. Several studies evidenced a link between p75NTR and the pathogenesis of prion diseases. In this study, we investigated the distribution of several neurotrophins and their receptors, including p75NTR, in the brain of naturally scrapie-affected sheep and experimentally infected ovinized transgenic mice and its correlation with other markers of prion disease. No evident changes in infected mice or sheep were observed regarding neurotrophins and their receptors except for the immunohistochemistry against p75NTR. Infected mice showed higher abundance of p75NTR immunostained cells than their non-infected counterparts. The astrocytic labeling correlated with other neuropathological alterations of prion disease. Confocal microscopy demonstrated the co-localization of p75NTR and the astrocytic marker GFAP, suggesting an involvement of astrocytes in p75NTR-mediated neurodegeneration. In contrast, p75NTR staining in sheep lacked astrocytic labeling. However, digital image analyses revealed increased labeling intensities in preclinical sheep compared with non-infected and terminal sheep in several brain nuclei. This suggests that this receptor is overexpressed in early stages of prion-related neurodegeneration in sheep. Our results confirm a role of p75NTR in the pathogenesis of classical ovine scrapie in both the natural host and in an experimental transgenic mouse model.

Highlights

Neurotrophins are a group of growth factors that exert important functions in the nervous system of vertebrates
P75NTR is able to interact with other membrane elements, including Trk receptors, in which case it increases their affinity for mature neurotrophins and contributes to prosurvival signaling [8,9], and with sortilin, which participates in the apoptosis outcome through not-yet clarified mechanisms [2,10]
Our results indicate that increased numbers of p75 neurotrophin receptor (p75NTR)-positive astrocytes are present in terminal stages of neurodegeneration in a murine model of scrapie

Summary

Introduction

Neurotrophins are a group of growth factors that exert important functions in the nervous system of vertebrates They are synthetized and secreted by neurons and other cell types and regulate critical processes, from neuron maturation and synaptic plasticity to maintenance of the nervous tissue during adulthood [1,2]. P75NTR is able to interact with other membrane elements, including Trk receptors, in which case it increases their affinity for mature neurotrophins and contributes to prosurvival signaling [8,9], and with sortilin, which participates in the apoptosis outcome through not-yet clarified mechanisms [2,10] For all these reasons, p75NTR is positioned at the crossroad between cell survival and death and has attracted interest due to its potential use as a biomarker for neurodegenerative disorders and, more importantly, as a therapeutic agent

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Results

Conclusion