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: The effects of sortilin deficiency on the expression of choline acetyltranferase (ChAT), in neurons of the nucleus basalis of Meynert (NBM) and of the medial septum/diagonal band of Broca (MS/DBH), were studied by ChAT immunohistochemistry. In the NBM of AD10, Sort1−/− and AD10×Sort1−/− mice, a significant decrease in the number of ChAT-immunoreactive neurons was first observed at 6 months of age (Fig. 3A and C; P < 0.05 versus WT mice). This decrease persisted in 12-month old AD10 mice (Fig. 3A and C, P < 0.05 versus WT mice) but was absent in age-matched Sort1−/− mice (Fig. 3A and C) and partially rescued in AD10×Sort1−/− mice (Fig. 3A and C). In the MS/DBH of AD10, as well as of Sort1−/− and AD10×Sort1−/− mice, cholinergic deficits appear earlier than in NBM, already at 3 months (Fig. 3B, P < 0.05 versus WT mice). 6 months old AD10 and AD10×Sort1−/− mice showed a further decrease in the number of MS/DBH cholinergic neurons (Fig. 3B, P < 0.05 versus WT mice), while Sort1−/− mice show normal levels (Fig. 3B). Twelve months old AD10 mice still showed a decreased number of ChAT-immunoreactive neurons (Fig. 3B and D, P < 0.05 versus WT mice, that was partially rescued in AD10×Sort1−/− mice and normal absent in Sort1−/− (Fig. 3B and D). We concluded that sortilin loss partially rescues AD10 mice from cholinergic deficit in the BF nucleus at late stages of neurodegeneration.
Affiliation: Laboratory of Neurobiology, Scuola Normale Superiore, Pisa, Italy.