Microglia Are Critical in Host Defense against Prion Disease.

Abstract

Microglial cells in the central nervous system play important roles in neurodevelopment and resistance to infection, yet microglia can become neurotoxic under some conditions. An early event during prion infection is the activation of microglia and astrocytes in the brain prior to damage or death of neurons. Previous prion disease studies using two different strategies to manipulate signaling through the microglial receptor CSF-1R reported contrary effects on survival from prion disease. However, in these studies, reductions of microglial numbers and function were variable, thus confounding interpretation of the results. In the present work, we used oral treatment with a potent inhibitor of CSF-1R, PLX5622, to eliminate 78 to 90% of microglia from cortex early during the course of prion infection. Oral drug treatment early after infection with the RML scrapie strain significantly accelerated vacuolation, astrogliosis, and deposition of disease-associated prion protein. Furthermore, drug-treated mice had advanced clinical disease requiring euthanasia 31 days earlier than untreated control mice. Similarly, PLX5622 treatment during the preclinical phase at 80 days postinfection with RML scrapie also accelerated disease and resulted in euthanasia of mice 33 days earlier than infected controls. PLX5622 also accelerated clinical disease after infection with scrapie strains ME7 and 22L. Thus, microglia are critical in host defense during prion disease. The early accumulation of PrPSc in the absence of microglia suggested that microglia may function by clearing PrPSc, resulting in longer survival.IMPORTANCE Microglia contribute to many aspects of health and disease. When activated, microglia can be beneficial by repairing damage in the central nervous system (CNS) or they can turn harmful by becoming neurotoxic. In prion and prionlike diseases, the involvement of microglia in disease is unclear. Previous studies suggest that microglia can either speed up or slow down disease. In this study, we infected mice with prions and depleted microglia from the brains of mice using PLX5622, an effective CSF-1R tyrosine kinase inhibitor. Microglia were markedly reduced in brains, and prion disease was accelerated, so that mice needed to be euthanized 20 to 33 days earlier than infected control mice due to advanced clinical disease. Similar results occurred when mice were treated with PLX5622 at 80 days after infection, which was just prior to the start of clinical signs. Thus, microglia are important for removing prions, and the disease is faster when microglia are depleted.

• Authors: James A Carroll, Brent Race, Katie Williams, James Striebel, Bruce Chesebro
• Journal: Journal of virology (J Virol) Vol. 92 Issue 15 (08 01 2018) ISSN: 1098-5514 [Electronic] United States
• PMID: 29769333 (Publication Type: Journal Article, Research Support, N.I.H., Intramural)
• Copyright: Copyright © 2018 American Society for Microbiology.

Chemical References

• Csf1r protein, mouse
• Organic Chemicals
• PLX5622
• PrPSc Proteins
• Receptors, Granulocyte-Macrophage Colony-Stimulating Factor

Topics

• Administration, Oral
• Animals
• Apoptosis
• Disease Models, Animal
• Female
• Male
• Mice
• Microglia (cytology, drug effects, metabolism, pathology)
• Organic Chemicals (administration & dosage, adverse effects)
• PrPSc Proteins (metabolism)
• Receptors, Granulocyte-Macrophage Colony-Stimulating Factor (metabolism)
• Scrapie (chemically induced, metabolism, pathology)
• Severity of Illness Index