EVOLUTION OF NEUROPATHOLOGIC ABNORMALITIES ASSOCIATED WITH BLOOD-BRAIN-BARRIER BREAKDOWN IN TRANSGENIC MICE EXPRESSING INTERLEUKIN-6 IN ASTROCYTES

As both astrocytes and cytokines modulate the permeability of cerebral endothelial cells, transgenic animal models which overexpress cytokin es, such as interleukin-6 (IL-6), may provide insight into the neuropa thological consequences of increased BBB permeability. In this study, a GFAP-IL6 transgenic mouse model and horseradish peroxidase (HRP) wer e used to investigate BBB permeability and associated neuropathologic changes. In the cerebellum of control mice, the BBB developed between postnatal days 7 and 14. In transgenic mice, the BBB never developed a nd extensive breakdown was evident in both high- and low-expressor ani mals by 1 month after blah. Vascular proliferation was apparent from b irth in association with development and retention of normal cerebella r architecture until 3 and 6 months in high- and low-expressor animals , respectively. At these times, a leptomeningeal inflammatory infiltra te, vacuolated astrocytic foot processes and endothelial abnormalities were apparent in the cerebellum. At 6 months in high-expressor and 12 months in low-expressor animals, parenchymal inflammation, gliosis, s pongiform change, axonal degeneration and macrophage accumulation were evident. The findings suggest that increased production of IL-6 can i nfluence the development and physiologic function of the BBB as well a s contribute to parenchymal central nervous system injury.