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Fibrillar prion peptide (106-126) and scrapie prion protein hamper phagocytosis in microglia
Jaroslava Ciesielski-Treska1, Nancy J Grant, Gabrielle Ulrich
1CNRS UPR-2356 Neurotransmission et Sécrétion Neuroendocrine, IFR 37 des Neurosciences Centre de Neurochimie, Strasbourg, France. ciesielski-treska@neurochem.u-strasbg.fr
Abstract:
The inflammatory response in prion diseases is dominated by microglial activation. As macrophages of the central nervous system, the phagocytic capacity of microglia is well recognized, and it is possible that microglia are involved in the removal and processing of amyloid fibrils, thus preventing their harmful effect. We have analyzed the effects of a synthetic peptide of the human prion protein, PrP(106-126), which can form fibrils, and the pathogenic form of prion protein, PrPsc, on phagocytosis in microglia isolated from neonatal rat brain cultures. To some extent, fibrillar PrP(106-126) is internalized and processed. However, both synthetic prion peptide PrP(106-126) in a fibrillar form and pathogenic prion protein PrPsc severely hamper the phagocytic activity as measured by the uptake of beads by microglia. At a concentration that does not induce microglial death, PrP(106-126) reduced the number of beads internalized and altered their cytoplasmic distribution. This effect was not due to decreased binding of beads to the cell surface, nor restricted to specific classes of receptors. Although the PrP(106-126) did not prevent F-actin and Rac1 accumulation at sites of particle engulfment, it appeared to interfere with a later step of the internalization process.
Insights
Prion diseases involve microglial activation. Both synthetic prion peptide and pathogenic prion protein impair microglial phagocytosis, hindering their ability to clear harmful protein aggregates.
Area of Science:
- Neuroscience
- Immunology
- Biochemistry
Background:
- Prion diseases are characterized by neuroinflammation, with microglia, the central nervous system's immune cells, playing a key role.
- Microglia possess phagocytic capabilities, suggesting a potential role in clearing pathogenic protein aggregates like amyloid fibrils.
Purpose of the Study:
- To investigate the impact of a synthetic prion protein peptide (PrP(106-126)) and the pathogenic prion protein (PrPSc) on microglial phagocytosis.
- To determine if these prion protein forms interfere with the microglial clearance of potentially harmful aggregates.
Main Methods:
- Primary microglia were isolated from neonatal rat brain cultures.
- Phagocytic activity was assessed by measuring the uptake of beads by microglia.
- The effects of fibrillar PrP(106-126) and PrPSc on bead internalization and distribution were analyzed.
Main Results:
- Fibrillar PrP(106-126) was partially internalized and processed by microglia.
- Both fibrillar PrP(106-126) and PrPSc significantly inhibited microglial phagocytic activity, reducing bead uptake.
- PrP(106-126) altered the cytoplasmic distribution of internalized beads without affecting initial binding or F-actin/Rac1 accumulation.
Conclusions:
- Synthetic prion peptides and pathogenic prion proteins can severely impair microglial phagocytosis.
- This impairment occurs at a late stage of the internalization process, potentially hindering the clearance of toxic prion aggregates.
- Understanding these mechanisms is crucial for developing therapeutic strategies for prion diseases.
