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Prion peptide uptake in microglial cells--the effect of naturally occurring autoantibodies against prion protein
Yvonne Roettger1, Inga Zerr, Richard Dodel
1Department of Neurology, Philipps-University Marburg, Marburg, Germany.
Abstract:
In prion disease, a profound microglial activation that precedes neurodegeneration has been observed in the CNS. It is still not fully elucidated whether microglial activation has beneficial effects in terms of prion clearance or whether microglial cells have a mainly detrimental function through the release of pro-inflammatory cytokines. To date, no disease-modifying therapy exists. Several immunization attempts have been performed as one therapeutic approach. Recently, naturally occurring autoantibodies against the prion protein (nAbs-PrP) have been detected. These autoantibodies are able to break down fibrils of the most commonly used mutant prion variant PrP106-126 A117V and prevent PrP106-126 A117V-induced toxicity in primary neurons. In this study, we examined the phagocytosis of the prion peptide PrP106-126 A117V by primary microglial cells and the effect of nAbs-PrP on microglia. nAbs-PrP considerably enhanced the uptake of PrP106-126 A117V without inducing an inflammatory response in microglial cells. PrP106-126 A117V uptake was at least partially mediated through scavenger receptors. Phagocytosis of PrP106-126 A117V with nAbs-PrP was inhibited by wortmannin, a potent phosphatidylinositol 3-kinase inhibitor, indicating a separate uptake mechanism for nAbs-PrP mediated phagocytosis. These data suggest the possible mechanisms of action of nAbs-PrP in prion disease.
Insights
Naturally occurring autoantibodies against the prion protein (nAbs-PrP) enhance microglial uptake of prion peptide PrP106-126 A117V without causing inflammation. This suggests a potential therapeutic mechanism for prion diseases.
Area of Science:
- Neuroscience
- Immunology
- Cell Biology
Background:
- Prion diseases involve microglial activation in the central nervous system (CNS), but their role in prion clearance versus detrimental inflammation is unclear.
- No disease-modifying therapies currently exist for prion diseases, prompting research into novel therapeutic approaches like immunotherapy.
- Naturally occurring autoantibodies against the prion protein (nAbs-PrP) have shown potential in breaking down prion fibrils and reducing toxicity.
Purpose of the Study:
- To investigate the phagocytosis of the prion peptide PrP106-126 A117V by primary microglial cells.
- To determine the effect of nAbs-PrP on microglial cells, specifically regarding prion peptide uptake and inflammatory responses.
- To elucidate the mechanisms underlying nAbs-PrP-mediated phagocytosis of prion peptides.
Main Methods:
- Primary microglial cells were used to study the phagocytosis of the prion peptide PrP106-126 A117V.
- The impact of nAbs-PrP on PrP106-126 A117V uptake and inflammatory cytokine release by microglia was assessed.
- Experiments involved using scavenger receptor pathways and wortmannin, a phosphatidylinositol 3-kinase inhibitor, to investigate uptake mechanisms.
Main Results:
- nAbs-PrP significantly enhanced the uptake of PrP106-126 A117V by microglial cells.
- This enhanced uptake did not trigger an inflammatory response in the microglial cells.
- Prion peptide uptake was partially mediated by scavenger receptors and involved a distinct phosphatidylinositol 3-kinase-dependent pathway when facilitated by nAbs-PrP.
Conclusions:
- nAbs-PrP can promote the clearance of prion peptides by microglia without inducing harmful inflammation.
- The findings suggest that nAbs-PrP may represent a promising therapeutic strategy for prion diseases by leveraging microglial phagocytosis.
- Understanding the specific uptake mechanisms of nAbs-PrP-mediated phagocytosis is crucial for developing targeted prion disease therapies.
