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. 2021 Mar 8;22(5):2714.
doi: 10.3390/ijms22052714.

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

Tomás Barrio  1 , Enric Vidal  2 , Marina Betancor  1 , Alicia Otero  1 , Inmaculada Martín-Burriel  3 , Marta Monzón  1 , Eva Monleón  1 , Martí Pumarola  4 , Juan José Badiola  1 , Rosa Bolea  1
Affiliations

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

Tomás Barrio et al. Int J Mol Sci. .

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.

Keywords: astrocyte; neurotrophin; p75NTR; prion disease; scrapie; transgenic mice.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
p75NTR receptor in the brain of infected and control mice and sheep. In the upper row (A,B,E,F), the general patterns (neuropil staining [not marked] and neuronal intracytoplasmic staining [asterisks]) observed in the two models are displayed, while the lower row (C,D,G) shows specifically the glial staining found in mice (arrows) and sheep (arrowheads). Microphotographs taken from medulla oblongata (A,B,D,E,F), corpus callosum (C), and hippocampus (G).
Figure 2
Figure 2
(A–F) Visual comparison of p75NTR glial immunolabeling between control (A,B), preclinical (C,D), and terminal mice (E,F). Notice the presence of more abundant and fibrous p75NTR-positive glial cells (purportedly astrocytes) in infected animals, together with the presence of vacuolization (spongiform lesion) in infected but not in control mice. (G) Semi-quantification of glial p75NTR labeling in ten brain areas. Mobl: medulla oblongata, Cb: cerebellar cortex, Mes: mesencephalon, Hy: hypothalamus, Th: thalamus, Hp: hippocampus, Tc: parietal and temporal cortices at the level of thalamus, Str: striatum, Sn: septal nuclei, Fc: frontal cortex. Error bars represent SEM. Kruskal–Wallis test followed by Dunn’s post-hoc pairwise comparison, * p ≤ 0.05, ** p ≤ 0.01.
Figure 3
Figure 3
Image analysis of p75NTR immunostaining in sheep brains showed significant differences between groups of animals in several brain areas and nuclei. The upper panel (framed) represents the overall staining in the different brain areas (Mobl: medulla oblongata, Pons: pons, Cb: cerebellum, Mes: mesencephalon, Di: diencephalon, Str: striatum, Fc: frontal cortex), while the lower panels (non-framed), show the staining in specific nuclei within those regions (Cune: cuneate nucleus, DMNV: dorsal motor nucleus of the vagus, Hypg: hypoglossal nucleus, Retc: reticular formation, Fac: facial nucleus, Vestb: vestibular nucleus, SupCol: superior colliculus, SNigra: substantia nigra, Hy: hypothalamus, Th DL: dorsolateral nuclei of thalamus, Th DM: dorsomedial nuclei of thalamus, Th Ven: ventral nuclei of thalamus, Sept: septal area, Lent: lenticular nucleus, Caud: caudate nucleus). The height of the bars represents the mean optical density (OD). Error bars represent SEM. Kruskal–Wallis test followed by Dunn’s post-hoc pairwise comparison, * p ≤ 0.05, ** p ≤ 0.01.
Figure 4
Figure 4
Comparison between p75NTR, GFAP, and NeuN immunostaining patterns in mice. Immunohistochemistry against p75NTR (A,B), GFAP (C,D), or NeuN (E,F) in corpus callosum (A,C,E) and in medulla oblongata (B,D,F). Notice that p75NTR labels both glial cells (probably astrocytes) (A, arrowheads) and neurons (B, arrows), while GFAP targets astrocytes (C, arrowheads) but not other cell types (D). Importantly, GFAP-positive astrocytes (C, arrowheads) are more abundant than p75NTR-positive glial cells (A, arrowheads), suggesting that only a subpopulation of astrocytes express p75NTR.
Figure 5
Figure 5
Comparison between p75NTR (A–C) and GFAP immunostaining (D–F) patterns in control (A,B,D,E) and infected (C,F) sheep. Notice the higher abundance of GFAP-positive reactive astrocytes (astrogliosis) in infected mice, and the lack of correlation between p75NTR and GFAP distribution patterns, indicative of the fact that ovine astrocytes do not express significant levels of the receptor. Microphotographs taken from hippocampus.
Figure 6
Figure 6
Distribution of spongiform change (A), PrPSc deposits (B), and gliosis (C) in comparison with the distribution of glial p75NTR labeling in the brain of control, preclinical, and terminal mice. Notice the overlapping of the curves representing the three parameters and the bars representing glial p75NTR staining intensity. Positive Spearman’s correlation coefficients (r) were obtained in each case, which were highly significant (p < 0.0001). Mobl: medulla oblongata, Cb: cerebellar cortex, Mes: mesencephalon, Hy: hypothalamus, Th: thalamus, Hp: hippocampus, Tc: parietal and temporal cortices at the level of thalamus, Str: striatum, Sn: septal nuclei, Fc: frontal cortex. Error bars represent SEM.
Figure 7
Figure 7
Confocal microscopy for p75NTR (green) and PrP (red) in sheep brain samples. Notice that p75NTR distribution patterns agreed with those observed by IHC, including neuropil and perineuronal staining (A), glial staining (probably oligodendrocytes) (B), and neuronal intracytoplasmic staining with evidence of neuron processes (C). Co-localization of p75NTR with PrP, although observed in several cases (D–F), was not the general rule.
Figure 8
Figure 8
Confocal microscopy for GFAP (red) and p75NTR (green) in sheep (A) and mouse (B) brain samples. Notice the lack of correlation between both markers in sheep tissues and the clear co-localization that in contrast is observed in mice, suggesting that mouse but not sheep astrocytes express detectable levels of p75NTR.
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