Transmissible spongiform encephalopathies (TSEs) are epidemic neurodegenerative diseases caused by prion proteins; in particular, they are induced by misfolded prion proteins (PrPSc). PrPSc tend to aggregate into insoluble amyloid prion fibrils (fPrPWT), resulting in apoptosis of neuron cells and sequential neurodegeneration. Previous studies indicate that microglia cells play an important role in the innate immune system, and that these cells have good neuroprotection and delay the onset of TSEs. However, microglia can be a double-sided blade. For example, both Cu2+ and Mn2+ can induce microglia activation and secrete many inflammatory cytokines that are fatal to neuron cells. Unfortunately, PrP have cation binding sites at the N-terminus. When PrPSc accumulate during microglial phagocytosis, microglia may change the phenotype to secrete pro-inflammation cytokines, which increases the severity of the disease. Some studies have revealed an increase in the concentration of Mn2+ in the brains of patients. In this study, we treated microglia with fPrPWT and cations and determined IκBα and IL-1β expression by Western blotting and quantitative polymerase chain reaction. The results showed that Mn–fPrPWT decreased IκBα levels and dramatically increased IL-1β mRNA expression. In addition, competing binding between Cu2+ and Mn2+ can decrease the effect of Mn–fPrPWT on IκBα and IL-1β. The effects of divalent cations and fPrPWT in microglia inflammation are also discussed.