The Effects of Divalent Cation-Chelated Prion Fibrils on the Immune Response of EOC 13.31 Microglia Cells
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Updated: Dec 5, 2025
Author Spotlight: Insight Into Advances in Prion Diseases Research
Published on: August 11, 2023
Huan-I Jen1, Zih-You Lin1, Jin-Xun Guo1
1Department of Biomedical Sciences, National Chung Cheng University, 168 University Road, Min-Hsiung Chia-Yi 62102, Taiwan.
Abstract:
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.
Insights
Manganese and misfolded prion proteins (PrPSc) activate microglia, increasing neuroinflammation and disease severity in transmissible spongiform encephalopathies (TSEs). Copper can counteract these harmful effects.
Area of Science:
- Neuroscience
- Immunology
- Biochemistry
Background:
- Transmissible spongiform encephalopathies (TSEs) are neurodegenerative diseases caused by misfolded prion proteins (PrPSc).
- Microglia play a dual role in neuroprotection and neuroinflammation, influenced by cations like Mn2+ and Cu2+.
- Prion protein N-termini bind cations, potentially altering microglia function during disease.
Purpose of the Study:
- To investigate the combined effects of misfolded prion protein fibrils (fPrPWT) and manganese (Mn2+) on microglia.
- To examine the impact of copper (Cu2+) as a competitor to manganese in modulating these effects.
- To determine the expression levels of IκBα and IL-1β in microglia under these conditions.
Main Methods:
- Treatment of microglia with fPrPWT and divalent cations (Mn2+, Cu2+).
- Analysis of IκBα protein levels using Western blotting.
- Quantification of IL-1β mRNA expression via quantitative polymerase chain reaction.
Main Results:
- Mn-fPrPWT significantly decreased IκBα levels and increased IL-1β mRNA expression, indicating heightened inflammation.
- Competing binding of Cu2+ with Mn2+ mitigated the pro-inflammatory effects of Mn-fPrPWT.
- These findings highlight the complex interplay between prion proteins, cations, and microglia activation.
Conclusions:
- Manganese exacerbates prion-induced microglia inflammation, contributing to neurodegeneration in TSEs.
- Copper acts as a protective agent by competing with manganese binding sites.
- Understanding these interactions is crucial for developing therapeutic strategies against prion diseases.
