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Pathogenesis of mouse scrapie: dynamics of vacuolation in brain and spinal cord after intraperitoneal infection
Abstract:
At the late clinical stage of scrapie in mice, the severity and distribution of vacuolation in the brain (the lesion profile) is largely determined by the strain of agent and the genotype of the mouse: under controlled conditions, lesion profiles can be used to distinguish between scrapie strains. This paper describes the sequential development of lesions in brain at much earlier times and includes a study of spinal cord. Mice (CW) were infected intraperitoneally with 139A scrapie. Grey matter vacuolation first occurred in thoracic cord, developing later in lumbar and cervical cords, and then in various brain regions in a caudal to rostral sequence. This pattern closely matches the sequential spread of infection from mid-thoracic cord to much of the CNS that was previously found in this scrapie model. Further studies of grey matter in spinal cord suggest that agent entered the mid-thoracic region via sympathetic fibres. Vacuolation in white matter mirrored the grey matter pattern within an area but always occurred later. The severity of grey matter vacuolation in the four areas of the CNS where it developed early, reached plateau levels before the clinical stage of scrapie, but the severity was still increasing at the clinical stage in areas where vacuolation had started late. Hence the severity of lesions in a particular area may sometimes be limited by the time available for them to develop before the host dies. It appears that the distribution of vacuolation in this particular scrapie model is initially influenced by that of the infectious agent and only later does it reflect the distribution of vacuolation target areas shown by the characteristic lesion profile.
Insights
Scrapie vacuolation in mice begins in the spinal cord and progresses to the brain, influenced by infection spread. Lesion severity depends on when and where vacuolation starts before the animal succumbs to disease.
Area of Science:
- Neuroscience
- Veterinary Pathology
- Prion Disease Research
Background:
- Scrapie lesion profiles in the brain are strain and host-dependent.
- Previous studies focused on late-stage vacuolation patterns.
Purpose of the Study:
- To investigate the early, sequential development of vacuolation in the central nervous system (CNS) of mice infected with scrapie.
- To examine the role of spinal cord and sympathetic fibers in the initial spread of infection.
- To correlate lesion development with the clinical progression of scrapie.
Main Methods:
- Intraperitoneal infection of CW mice with 139A scrapie agent.
- Microscopic examination of brain and spinal cord tissue to assess vacuolation severity and distribution.
- Analysis of lesion development over time, from early stages to the clinical phase.
Main Results:
- Grey matter vacuolation initiated in the thoracic spinal cord, spreading sequentially to lumbar, cervical cords, and then the brain in a caudal-to-rostral manner.
- Evidence suggests the scrapie agent may enter the CNS via sympathetic nerve fibers in the mid-thoracic region.
- White matter vacuolation followed grey matter patterns but with a delay.
- Lesion severity plateaued before clinical signs in early-affected areas, but continued to increase in late-affected areas.
Conclusions:
- The early distribution of scrapie vacuolation is primarily driven by the spread of the infectious agent, not solely by predetermined target areas.
- The timing of lesion development relative to the host's lifespan influences the ultimate severity of vacuolation in specific CNS regions.
- Understanding the sequential spread of prion diseases is crucial for interpreting neuropathological findings.