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.

Lymph nodal prion replication and neuroinvasion in mice devoid of follicular dendritic cells

“…Lymphoinvasion most likely plays an important role in the pathogenesis of vCJD, because prion infectivity can be detected in tonsils of virtually every vCJD patient (29,30). After lymphoinvasion, neuroinvasion occurs via autonomic nerves (31)(32)(33)(34)(35), but the nexus between germinal centers and nerves is still elusive. By virtue of their mobility, macrophages may represent a plausible candidate for transport of prion infectivity from germinal centers to sympathetic nerve terminals.…”

Incubation Periods and Survival Times for Mice Injected Stereotaxically with Three Scrapie Strains in Different Brain Regions

“…In the present study, it is probable that agent replication occurred first in the cerebellum and led to pathological changes. Subsequent spread to the forebrain was followed by replication of agent in that area but signs and symptoms developed before vacuolation could occur (Cole & Kimberlin, 1985). A time course study following stereotaxic injection of 22L in the cerebellum has been initiated recently to test this putative sequence of events.…”

“…The most plausible explanation for the discrepancy may lie in a difference in timing of replication and vacuolation. According to Cole & Kimberlin (1985), 139A injected i.p. in Compton White mice began to show vacuolation in the brain stem which gradually spread to the forebrain regions.…”

Western Blot Detection of Scrapie-associated Fibril Protein in Tissues outside the Central Nervous System from Preclinical Scrapie-infected Mice

“…This is presumably a consequence of the relatively late appearance of infectivity in the central nervous system of i.p. infected mice (Eklund et al, 1967;Cole & Kimberlin, 1985 ;Kimberlin & Walker, 1979). In lymph node samples, SAF proteins were detected faintly in those from the groups sacrificed at 6, 18 and 24 weeks p.i.…”