Dissecting the role of sortilin receptor signaling in neurodegeneration induced by NGF deprivation.
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.
Affiliation: Laboratory of Neurobiology, Scuola Normale Superiore, Pisa, Italy.Show MeSH
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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 . 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 ), 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.
Affiliation: Laboratory of Neurobiology, Scuola Normale Superiore, Pisa, Italy.