Abnormal Changes of IL3/IL3R and Its Downstream Signaling Pathways in the Prion-Infected Cell Line and in the Brains of Scrapie-Infected Rodents

Abstract

Interleukin 3 (IL-3) plays an important role in hematopoiesis and immune regulation, brain IL-3/IL-3R signaling has been shown to involve in the physiological and pathological processes of a variety of neurodegenerative diseases, but its role in prion diseases is rarely described. Here, the changes of IL-3/IL-3R and its downstream signaling pathways in a scrapie infected cell line and in the brains of several scrapie infected rodent models were evaluated by various methods. Markedly decreased IL-3Rα were observed in the brains of scrapie infected rodents at terminal stage and in the prion infected cell model, which showed increased in the brain samples collected at early and middle stage of infection. The IL-3 levels were almost unchanged in the brains of scrapie infected mice and in the prion infected cell line. Morphological assays identi ed close co-localization of the increased IL-3Rα signals with NeuN-andIba1-positive cells, whereas co-localization of IL-3 signals with NeuN-and GFAP-positive cells in the scrapie infected brain tissues. Some downstream components of IL-3/IL-3R pathways, including JAK2-STAT5 and PI3K/AKT/mTOR pathways, were downregulated in the brains of scrapie infected rodents at terminal stage and in the prion infected cells. Stimulation of recombinant IL-3 on the cultured cells showed prion that the prion infected cells displayed markedly more reluctant responses of JAK2-STAT5 and PI3K/AKT/mTOR pathways than the normal partner cells. These data suggest that although prion infection or PrP Sc accumulation in brain tissues does not affect IL-3 expression, it signi cantly downregulates IL-3R levels, thereby inhibiting the downstream pathways of IL-3/IL-3R and blocking the neuroregulatory and neuroprotective activities of IL-3.

Aberrance of GAP43/p-GAP43 closely associates with the pathology of neuron loss in prion-infected rodent models

“…However, completely opposite pro le of GAP43 expression is repeatedly observed in the brain tissues of prion diseases at nal stage, including the scrapie infected rodent models in this study and the different types of human prion diseases [14,15]. Coincidentally, our previous studies have con rmed that the NF-κB pathway and its downstream key proteins PI3K and AKT in the brains of prion infected mice is signi cantly inhibited [36,37]. We think such diversity is reasonable, as the neurons, marked with GAP43 expression, in the context of brain tissues cannot to further duplicate themselves in vivo.…”