Remarkable impairment of Wnt/-catenin signaling in the brains of the mice infected with scrapie agents

摘要

Prion diseases are a group of neurodegenerative diseases characterized by neuronal loss and spongiform degeneration, astrogliosis and aggregation of scrapie prion protein (PrPSc) in the central nervous system (CNS). The Wnt signaling pathway is a highly evolutionarily conserved pathway in eukaryotes that regulates cell proliferation, differentiation and survival. Impairment of Wnt/-catenin signaling has been reported in the CNS of various neurodegenerative diseases, such as Alzheimer's disease and Parkinson's disease. To investigate the functional state of Wnt/-catenin signaling in the CNS tissues during the progression of prion disease, the components of Wnt/-catenin signaling in the brains of the scrapie agents 139A- and ME7-infected mice were evaluated. Compared with the normal controls, the brain levels of phosphor--catenin (Ser(33,37) and Thr(41)) in 139A- and ME7-infected mice were significantly increased, while those of cyclin D1, which is one of the target genes of Wnt signaling, were decreased. The levels of phosphor-glycogen synthase kinase-3 (GSK-3) Ser(9) were markedly reduced, representing an enhanced GSK-3 activity in scrapie-infected mice. Both western blot and immunohistochemical assays revealed a remarkable increase of Dickkopf-1, the antagonist of Wnt/-catenin signaling, in the brains of scrapie-infected anim-als, which co-localized well with the remaining neurons in theimmunofluorescent tests. We also observed slightly decreased Wnt-3 and unchanged disheveled-3 (Dvl-3) in the brains of the infected mice. Our data, here, strongly indicate an impairment of Wnt/-catenin pathway in the brains of prion disease, which shows a time-dependent progression along with the incubation period.