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MCP-1 and murine prion disease: separation of early behavioural dysfunction from overt clinical disease
L M Felton1, C Cunningham, E L Rankine
1CNS Inflammation Group, School of Biological Sciences, University of Southampton, Southampton, SO16 7PX, UK. lmf1@soton.ac.uk
Abstract:
Prion diseases are chronic, fatal neurodegenerative conditions of the CNS. We have investigated the role of monocyte chemoattractant protein-1 (MCP-1) in the ME7 model of murine prion disease. MCP-1 expression increased in the CNS throughout disease progression and was positively correlated with microglial activation. We subsequently compared the inflammatory response, pathology and behavioural changes in wild-type (wt) mice and MCP-1 knockout mice (MCP-1-/-) inoculated with ME7. Late-stage clinical signs were delayed by 4 weeks in MCP-1-/- mice, and survival time increased by 2-3 weeks. By contrast, early changes in affective behaviours and locomotor activity were not delayed in onset. There was also no difference in microglial activation or neuronal death in the hippocampus and thalamus of wt mice and MCP-1-/- mice. These results highlight an important dissociation between prolonged survival, early behavioural dysfunction and hippocampal/thalamic pathology when considering therapeutic intervention for human prion diseases and other chronic neurodegenerative conditions.
Insights
Monocyte chemoattractant protein-1 (MCP-1) influences prion disease progression. While MCP-1 knockout mice showed delayed late-stage symptoms and increased survival, early behavioral changes and neurodegeneration were unaffected.
Area of Science:
- Neuroscience
- Immunology
- Pathology
Background:
- Prion diseases are fatal, chronic neurodegenerative disorders affecting the central nervous system (CNS).
- Microglial activation and neuroinflammation are key features of prion disease pathogenesis.
- Monocyte chemoattractant protein-1 (MCP-1) is a key chemokine involved in inflammatory responses.
Purpose of the Study:
- To investigate the role of MCP-1 in the ME7 model of murine prion disease.
- To determine the impact of MCP-1 deficiency on disease progression, pathology, and behavior.
- To explore therapeutic implications for human prion diseases and other neurodegenerative conditions.
Main Methods:
- Utilized the ME7 model of prion disease in mice.
- Quantified MCP-1 expression in the CNS during disease progression.
- Compared wild-type (wt) mice with MCP-1 knockout (MCP-1-/-) mice regarding inflammatory response, pathology, and behavioral changes.
Main Results:
- MCP-1 expression increased in the CNS correlating positively with microglial activation.
- MCP-1-/- mice exhibited delayed late-stage clinical signs by 4 weeks and increased survival by 2-3 weeks.
- Early behavioral deficits and hippocampal/thalamic microglial activation or neuronal death were not significantly different between wt and MCP-1-/- mice.
Conclusions:
- MCP-1 plays a significant role in modulating the progression and survival in prion disease.
- There is a dissociation between prolonged survival, early behavioral dysfunction, and specific neuropathological changes.
- These findings suggest distinct therapeutic targets for managing different aspects of prion and other chronic neurodegenerative diseases.
