Increased c-Fos protein in the brains of scrapie-infected SAMP8, SAMR1, AKR and C57BL mice.

Abstract

Scrapie is a neurodegenerative disease that occurs naturally in sheep and goats. The histopathological changes include vacuolation, neuronal apoptosis and astrocytosis. The mechanisms involved in neuronal apoptosis are still unknown. Recently, we observed that activated p38 immunohistostaining was increased in scrapie-infected mice. In many neurodegenerative diseases, activation of the p38 pathway and of the immediate-early gene termed c-Fos appears to be required for the initiation of apoptosis. There are similarities in histopathological changes seen in scrapie-infected mice and in an uninfected senescence-accelerated mouse strain (SAMP8). This led us to investigate c-Fos protein levels in the brains of both uninfected and scrapie-infected SAMP8, SAMR1, AKR and C57BL mice using immunohistochemical methods. The SAMR1 strain served as a control in that it is a mouse strain that does not show accelerated ageing, but has a background that is similar to the SAMP8 strain. AKR was used because it is one of the progenitor strains of both SAM strains and, finally, C57BL is a completely unrelated strain. The results showed a low basal c-Fos expression in controls and a marked increase in c-Fos staining in scrapie-infected mice. In scrapie-positive mice, c-Fos immunoreactivity was observed in neurones in the cortex, hippocampus, thalamus, hypothalamus, medulla, midbrain, brainstem, paraterminal body, internal capsule and cerebellar Purkinje cells. Immunoreactivity of c-Fos was also observed in astrocytes in many brain areas of scrapie-infected mice, particularly in the hippocampus and cortex. Our results show that normal mouse brain (NMB)-injected AKR and SAMP8 mice had more c-Fos production than NMB-injected SAMR1 or C57BL mice; scrapie-infection induces significant increases in c-Fos immunoreactivity in all four mouse strains. Our study suggests that the increase in c-Fos levels may play a role in the neuronal apoptosis observed in scrapie-infected mice.