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Dissecting the role of sortilin receptor signaling in neurodegeneration induced by NGF deprivation.

Capsoni S, Amato G, Vignone D, Criscuolo C, Nykjaer A, Cattaneo A - Biochem. Biophys. Res. Commun. (2013)

Bottom Line: Sortilin is a member of the family of vacuolar protein sorting 10 protein domain receptors which has emerged as a co-receptor in cell death and neurodegeneration processes mediated by proneurotrophins.A protective effect was observed on non-spatial memory as assessed by novel object recognition, and histopathologically at the level of Aβ and BFCNs, while the phosphotau increase was unaltered by knocking out sortilin.We suggest that sortilin might be involved in different aspects of neurodegeneration in a complex way, supporting the view that sortilin functions in the CNS are broader than being a co-receptor in proneurotrophin and neurotrophin signaling.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Neurobiology, Scuola Normale Superiore, Pisa, Italy.

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Measurements of APP/Aβ clusters of dystrophic neurites in the hippocampus and of phosphorylated tau in lateral entorhinal cortex. (A) Quantification of the number of clusters at 3, 6 and 12 months of age. (B–D) Qualitative images of APP/Aβ amyloid clusters in (B) AD10, (C) Sort1−/− and (D) AD10×Sort1−/− hippocampus at 12 months of age. (E–G) Qualitative images of phosphotau-imunoreactive neurons in the lateral entorhinal cortex from (E) AD10 (E) Sort1−/− and (G) AD10×Sort1−/− mice at 12 months of age. (H) Quantification of the number of phospho-immunoreactive neurons at 3, 6 and 12 months of age in the LEC. All transgenic mice show an increase of phospho-tau immunoreactive neurons from 3 months of age with respect to WT mice. Bars are representative of mean  ± SEM. ∗P < 0.05 versus WT mice. #P < 0.05 versus AD10 and Sort1−/− mice. Scale bar = 250 μm.
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f0010: Measurements of APP/Aβ clusters of dystrophic neurites in the hippocampus and of phosphorylated tau in lateral entorhinal cortex. (A) Quantification of the number of clusters at 3, 6 and 12 months of age. (B–D) Qualitative images of APP/Aβ amyloid clusters in (B) AD10, (C) Sort1−/− and (D) AD10×Sort1−/− hippocampus at 12 months of age. (E–G) Qualitative images of phosphotau-imunoreactive neurons in the lateral entorhinal cortex from (E) AD10 (E) Sort1−/− and (G) AD10×Sort1−/− mice at 12 months of age. (H) Quantification of the number of phospho-immunoreactive neurons at 3, 6 and 12 months of age in the LEC. All transgenic mice show an increase of phospho-tau immunoreactive neurons from 3 months of age with respect to WT mice. Bars are representative of mean  ± SEM. ∗P < 0.05 versus WT mice. #P < 0.05 versus AD10 and Sort1−/− mice. Scale bar = 250 μm.

Mentions: To examine the influence of sortilin gene inactivation on the amyloid pathology in AD10 mice, we evaluated the number of clusters of dystrophic neurites immunoreactive for Aβ/APP, which appear in the 6 months-old AD10 hippocampus [8]. The number of Aβ/APP clusters was not significantly different in 3 months old AD10, Sort1−/− or AD10×Sort1−/− mice, with respect to WT (Fig. 2A). 6 months old AD10 mice showed the expected increase in the number of Aβ/APP clusters compared to WT (Fig. 2A, P < 0.05 and [8]), Sort1−/− have the same number of Aβ/APP clusters as WT mice, while AD10×Sort1−/− mice showed an equivalent number of Aβ/APP clusters to AD10 mice (Fig. 2A). However, at 12 months of age, sortilin loss in AD10 mice resulted in a twofold decrease in the number of Aβ/APP clusters compared to AD10 mice (Fig. 2A, B and D). Surprisingly, at 12 months, Sort1−/− mice showed an equivalent number of Aβ/APP immunoreactive dystrophic neurites to age-matched AD10 mice (Fig. 2A–C). Thus, inactivation of sortilin in AD10 mice delays the amyloidogenic process, determining a marked protection at 12 months of age. However, at this age, sortilin loss perse, appears to be amyloidogenic.


Dissecting the role of sortilin receptor signaling in neurodegeneration induced by NGF deprivation.

Capsoni S, Amato G, Vignone D, Criscuolo C, Nykjaer A, Cattaneo A - Biochem. Biophys. Res. Commun. (2013)

Measurements of APP/Aβ clusters of dystrophic neurites in the hippocampus and of phosphorylated tau in lateral entorhinal cortex. (A) Quantification of the number of clusters at 3, 6 and 12 months of age. (B–D) Qualitative images of APP/Aβ amyloid clusters in (B) AD10, (C) Sort1−/− and (D) AD10×Sort1−/− hippocampus at 12 months of age. (E–G) Qualitative images of phosphotau-imunoreactive neurons in the lateral entorhinal cortex from (E) AD10 (E) Sort1−/− and (G) AD10×Sort1−/− mice at 12 months of age. (H) Quantification of the number of phospho-immunoreactive neurons at 3, 6 and 12 months of age in the LEC. All transgenic mice show an increase of phospho-tau immunoreactive neurons from 3 months of age with respect to WT mice. Bars are representative of mean  ± SEM. ∗P < 0.05 versus WT mice. #P < 0.05 versus AD10 and Sort1−/− mice. Scale bar = 250 μm.
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f0010: Measurements of APP/Aβ clusters of dystrophic neurites in the hippocampus and of phosphorylated tau in lateral entorhinal cortex. (A) Quantification of the number of clusters at 3, 6 and 12 months of age. (B–D) Qualitative images of APP/Aβ amyloid clusters in (B) AD10, (C) Sort1−/− and (D) AD10×Sort1−/− hippocampus at 12 months of age. (E–G) Qualitative images of phosphotau-imunoreactive neurons in the lateral entorhinal cortex from (E) AD10 (E) Sort1−/− and (G) AD10×Sort1−/− mice at 12 months of age. (H) Quantification of the number of phospho-immunoreactive neurons at 3, 6 and 12 months of age in the LEC. All transgenic mice show an increase of phospho-tau immunoreactive neurons from 3 months of age with respect to WT mice. Bars are representative of mean  ± SEM. ∗P < 0.05 versus WT mice. #P < 0.05 versus AD10 and Sort1−/− mice. Scale bar = 250 μm.
Mentions: To examine the influence of sortilin gene inactivation on the amyloid pathology in AD10 mice, we evaluated the number of clusters of dystrophic neurites immunoreactive for Aβ/APP, which appear in the 6 months-old AD10 hippocampus [8]. The number of Aβ/APP clusters was not significantly different in 3 months old AD10, Sort1−/− or AD10×Sort1−/− mice, with respect to WT (Fig. 2A). 6 months old AD10 mice showed the expected increase in the number of Aβ/APP clusters compared to WT (Fig. 2A, P < 0.05 and [8]), Sort1−/− have the same number of Aβ/APP clusters as WT mice, while AD10×Sort1−/− mice showed an equivalent number of Aβ/APP clusters to AD10 mice (Fig. 2A). However, at 12 months of age, sortilin loss in AD10 mice resulted in a twofold decrease in the number of Aβ/APP clusters compared to AD10 mice (Fig. 2A, B and D). Surprisingly, at 12 months, Sort1−/− mice showed an equivalent number of Aβ/APP immunoreactive dystrophic neurites to age-matched AD10 mice (Fig. 2A–C). Thus, inactivation of sortilin in AD10 mice delays the amyloidogenic process, determining a marked protection at 12 months of age. However, at this age, sortilin loss perse, appears to be amyloidogenic.

Bottom Line: Sortilin is a member of the family of vacuolar protein sorting 10 protein domain receptors which has emerged as a co-receptor in cell death and neurodegeneration processes mediated by proneurotrophins.A protective effect was observed on non-spatial memory as assessed by novel object recognition, and histopathologically at the level of Aβ and BFCNs, while the phosphotau increase was unaltered by knocking out sortilin.We suggest that sortilin might be involved in different aspects of neurodegeneration in a complex way, supporting the view that sortilin functions in the CNS are broader than being a co-receptor in proneurotrophin and neurotrophin signaling.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Neurobiology, Scuola Normale Superiore, Pisa, Italy.

Show MeSH
Related in: MedlinePlus