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Published on: April 13, 2017
Microglia deficiency accelerates prion disease but does not enhance prion accumulation in the brain
Barry M Bradford1, Lynne I McGuire1, David A Hume2
1The Roslin Institute and R(D)SVS, University of Edinburgh, Easter Bush Campus, Midlothian, UK.
Abstract:
Prion diseases are transmissible, neurodegenerative disorders associated with misfolding of the prion protein. Previous studies show that reduction of microglia accelerates central nervous system (CNS) prion disease and increases the accumulation of prions in the brain, suggesting that microglia provide neuroprotection by phagocytosing and destroying prions. In Csf1rΔFIRE mice, the deletion of an enhancer within Csf1r specifically blocks microglia development, however, their brains develop normally and show none of the deficits reported in other microglia-deficient models. Csf1rΔFIRE mice were used as a refined model in which to study the impact of microglia-deficiency on CNS prion disease. Although Csf1rΔFIRE mice succumbed to CNS prion disease much earlier than wild-type mice, the accumulation of prions in their brains was reduced. Instead, astrocytes displayed earlier, non-polarized reactive activation with enhanced phagocytosis of neuronal contents and unfolded protein responses. Our data suggest that rather than simply phagocytosing and destroying prions, the microglia instead provide host-protection during CNS prion disease and restrict the harmful activities of reactive astrocytes.
Insights
Microglia protect the host during prion disease by restricting harmful astrocyte activation, rather than solely clearing prions. This finding advances understanding of neurodegenerative disease mechanisms.
Area of Science:
- Neuroscience
- Immunology
- Prion biology
Background:
- Prion diseases are fatal neurodegenerative disorders.
- Microglia are immune cells in the central nervous system (CNS).
- Previous research suggested microglia protect the CNS by clearing prions.
Purpose of the Study:
- To investigate the role of microglia in prion disease using a novel mouse model.
- To determine if microglia are essential for host protection against prion-induced neurodegeneration.
Main Methods:
- Utilized Csf1rΔFIRE mice, which lack microglia but have normal brain development.
- Inoculated Csf1rΔFIRE and wild-type mice with prions.
- Analyzed prion accumulation, disease progression, and cellular responses in the brain.
Main Results:
- Csf1rΔFIRE mice developed prion disease faster but had reduced prion accumulation.
- Astrocytes in Csf1rΔFIRE mice showed early reactive activation and phagocytosis.
- Microglia appear to provide host protection and limit detrimental astrocyte activity.
Conclusions:
- Microglia play a crucial protective role in prion disease, distinct from simple prion clearance.
- Microglia modulate astrocyte responses, preventing harmful neuroinflammation.
- Targeting microglia-astrocyte interactions may offer therapeutic strategies for prion diseases.
