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PrP deposition, microglial activation, and neuronal apoptosis in murine scrapie
A Williams1, P J Lucassen, D Ritchie
1Institute for Animal Health, BBSRC & MRC Neuropathogenesis Unit, Edinburgh, United Kingdom.
Abstract:
The present study investigated the relationship among PrP deposition, microglial activation, vacuolation, and neuronal death in the hippocampus of the 301V/VM murine scrapie model (mean incubation period 117 +/- 1 days). PrP deposition was first detected after 30 days and microglial activation after 60 days. Vacuolation in the CA1 and CA2 pyramidal layer was present from 90 days onward. Only occasional in situ end labeling (ISEL)-positive neurons were present in the hippocampus of scrapie-infected mice from 75 days postinoculation (d.p.i.), except at 105 d.p.i. when relatively large numbers of apoptotic, ISEL-positive neurons in the CA1 hippocampal region were observed. Terminally ill animals showed almost complete loss of CA1 pyramidal neurons. Electron microscopy of the CA1 region at 105 days confirmed that these neurons were dying by apoptosis. These data suggest that microglial activation in scrapie is a response to abnormal PrP deposition rather than a response to neuronal cell loss.
Insights
Microglial activation in scrapie models is a response to abnormal prion protein (PrP) deposition, not neuronal loss. This study tracks PrP accumulation, microglial response, and neuronal apoptosis in the hippocampus.
Area of Science:
- Neuroscience
- Pathology
- Prion Diseases
Background:
- Scrapie is a fatal neurodegenerative disease caused by prions.
- The relationship between prion protein (PrP) deposition, neuroinflammation, and neuronal death is not fully understood.
- Murine scrapie models are crucial for studying disease mechanisms.
Purpose of the Study:
- To investigate the temporal relationship between PrP deposition, microglial activation, vacuolation, and neuronal apoptosis in the hippocampus of the 301V/VM murine scrapie model.
- To determine whether microglial activation precedes or follows neuronal cell loss.
- To elucidate the role of microglial activation in scrapie pathogenesis.
Main Methods:
- Utilized the 301V/VM murine scrapie model with a mean incubation period of 117 days.
- Monitored PrP deposition, microglial activation, and vacuolation over time post-inoculation.
- Employed in situ end labeling (ISEL) to detect apoptotic neurons.
- Conducted electron microscopy to confirm neuronal apoptosis.
Main Results:
- PrP deposition was detected by 30 days post-inoculation (d.p.i.), followed by microglial activation at 60 d.p.i.
- Vacuolation appeared in the CA1 and CA2 regions from 90 d.p.i. onwards.
- Apoptotic neurons were observed from 75 d.p.i., with a significant increase at 105 d.p.i. in the CA1 region, confirmed by electron microscopy.
- Terminally ill animals exhibited substantial loss of CA1 pyramidal neurons.
Conclusions:
- Microglial activation in scrapie appears to be a response to abnormal PrP deposition.
- Neuronal cell loss, particularly apoptosis, occurs later in the disease progression.
- These findings suggest that inflammation is initiated by prion pathology rather than secondary to neuronal death.
