85ece7feef375fe0ea8bb31261b41819 pmc_33800240.pdf 0568027b882494f8f07225352ac26582bb13da67 pmc_33800240.pdf 1079093524df37382c4727cc7b736f272fbff44db0c4d7ceff1b84fdf53a4f6f pmc_33800240.pdf Title: Evidence of p75 Neurotrophin Receptor Involvement in the Central Nervous System Pathogenesis of Classical Scrapie in Sheep and a Transgenic Mouse Model Subject: 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: prion disease; scrapie; neurotrophin; p75NTR; astrocyte; transgenic mice Author: Tomás Barrio, Enric Vidal, Marina Betancor, Alicia Otero, Inmaculada Martín-Burriel, Marta Monzón, Eva Monleón, Martí Pumarola, Juan José Badiola and Rosa Bolea Creator: LaTeX with hyperref Producer: pdfTeX-1.40.21 CreationDate: Mon Mar 8 10:58:06 2021 CET ModDate: Mon Mar 8 11:08:50 2021 CET Custom Metadata: no Metadata Stream: no Tagged: no UserProperties: no Suspects: no Form: none JavaScript: no Pages: 18 Encrypted: no Page size: 595.276 x 841.89 pts (A4) Page rot: 0 File size: 30305374 bytes Optimized: no PDF version: 1.7 name type encoding emb sub uni object ID ------------------------------------ ----------------- ---------------- --- --- --- --------- CMFVHJ+VnURWPalladioL Type 1 Custom yes yes no 10 0 SFMQVM+URWPalladioL-Ital Type 1 Custom yes yes no 15 0 RSSHYF+URWPalladioL-Bold Type 1 Custom yes yes no 20 0 XZRRDB+URWPalladioL-Roma Type 1 Custom yes yes no 24 0 JYPLJJ+VnURWPalladioL-Bold Type 1 Custom yes yes no 28 0 IRWHZX+TimesNewRomanPSMT Type 1C WinAnsi yes yes no 36 0 CKUPDE+TimesNewRomanPS-BoldItalicMT Type 1C WinAnsi yes yes no 39 0 MCBCCI+SourceSansRoman-Regular Type 1C Custom yes yes no 61 0 MCBCCM+SourceSansRoman.613wght Type 1C Custom yes yes no 65 0 MCBCCO+SourceSansRoman-Bold Type 1C Custom yes yes no 69 0 QPZFHW+EURM10 Type 1 Builtin yes yes no 81 0 FAYBPG+CMSY10 Type 1 Builtin yes yes no 103 0 Jhove (Rel. 1.28.0, 2023-05-18) Date: 2024-10-02 03:25:44 CEST RepresentationInformation: pmc_33800240.pdf ReportingModule: PDF-hul, Rel. 1.12.4 (2023-03-16) LastModified: 2023-03-31 12:09:23 CEST Size: 30305374 Format: PDF Version: 1.7 Status: Well-Formed and valid SignatureMatches: PDF-hul MIMEtype: application/pdf PDFMetadata: Objects: 433 FreeObjects: 17 IncrementalUpdates: 0 DocumentCatalog: PageLayout: SinglePage PageMode: UseNone Outlines: Item: Title: Introduction Destination: section.1 Item: Title: Results Destination: section.2 Children: Item: Title: Mapping of Neurotrophins and Neurotrophin Receptors in the Brain Reveals Different Staining Patterns Destination: subsection.2.1 Item: Title: Glial Immunostaining for p75NTR Is Increased in Terminally Scrapie-Infected Mice Destination: subsection.2.2 Item: Title: Global p75NTR Immunolabeling Is Not Altered by Disease Progression in Mice Destination: subsection.2.3 Item: Title: Global p75NTR Immunolabeling Is Increased in Several Brainstem Nuclei of Preclinical Scrapie Infected Sheep Destination: subsection.2.4 Item: Title: Similarities in the Distribution of p75NTR- and GFAP-Immunolabeled Glial Cells Suggest p75NTR Expression in Astrocytes from Mice, but Not Sheep Destination: subsection.2.5 Item: Title: Glial p75NTR Staining Pattern Correlates Positively with the Severity of Spongiosis, PrPSc Deposition, and Gliosis in Mice Destination: subsection.2.6 Item: Title: Spongiosis and PrPSc Deposits Do Not Correlate with Global p75NTR Labeling in Mice or Sheep Destination: subsection.2.7 Item: Title: Confocal Microscopy Confirms the Relationship between Glial p75NTR Patterns and Astrocytes in Mice, but Not Sheep Destination: subsection.2.8 Item: Title: Discussion Destination: section.3 Item: Title: Materials and Methods Destination: section.4 Children: Item: Title: Sheep Destination: subsection.4.1 Item: Title: Mice Destination: subsection.4.2 Item: Title: Ethics Destination: subsection.4.3 Item: Title: Tissue Processing Destination: subsection.4.4 Item: Title: Immunohistochemistry Destination: subsection.4.5 Item: Title: Hematoxylin-Eosin (H&E) Staining Destination: subsection.4.6 Item: Title: Paraffin-Embedded Tissue Blot Destination: subsection.4.7 Item: Title: Semi-Quantitative Assessments Destination: subsection.4.8 Item: Title: Image Analysis Destination: subsection.4.9 Item: Title: Statistics Destination: subsection.4.10 Item: Title: Confocal Microscopy Destination: subsection.4.11 Item: Title: References Destination: subsection.4.11 Info: Title: Evidence of p75 Neurotrophin Receptor Involvement in the Central Nervous System Pathogenesis of Classical Scrapie in Sheep and a Transgenic Mouse Model Author: Tomás Barrio, Enric Vidal, Marina Betancor, Alicia Otero, Inmaculada Martín-Burriel, Marta Monzón, Eva Monleón, Martí Pumarola, Juan José Badiola and Rosa Bolea Subject: 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: prion disease; scrapie; neurotrophin; p75NTR; astrocyte; transgenic mice Creator: LaTeX with hyperref Producer: pdfTeX-1.40.21 CreationDate: Mon Mar 08 10:58:06 CET 2021 ModDate: Mon Mar 08 11:08:50 CET 2021 ID: 0xfc6a61ad986adab59ef9f91eabcd423a, 0xfc6a61ad986adab59ef9f91eabcd423a Filters: FilterPipeline: FlateDecode Fonts: Type1: Font: BaseFont: QPZFHW+EURM10 FontSubset: true FirstChar: 12 LastChar: 22 FontDescriptor: FontName: QPZFHW+EURM10 Flags: Symbolic FontBBox: -32, -243, 1060, 720 FontFile: true Font: BaseFont: RSSHYF+URWPalladioL-Bold FontSubset: true FirstChar: 3 LastChar: 122 FontDescriptor: FontName: RSSHYF+URWPalladioL-Bold Flags: Symbolic FontBBox: -152, -301, 1000, 935 FontFile: true EncodingDictionary: Differences: true Font: BaseFont: FAYBPG+CMSY10 FontSubset: true FirstChar: 6 LastChar: 20 FontDescriptor: FontName: FAYBPG+CMSY10 Flags: Symbolic FontBBox: -29, -960, 1116, 775 FontFile: true Font: BaseFont: XZRRDB+URWPalladioL-Roma FontSubset: true FirstChar: 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