NR AOYF
AU Riemer,C.; Schultz,J.; Schwarz,A.; Burwinkel,M.; Bamme,T.; Lu,B.; Gerard,C.; Baier,M.
TI CXCR3 Is Involved In Glia-Activation During Scrapie Pathogenesis
QU International Conference - Prion diseases: from basic research to intervention concepts - TSE-Forum, 08.10.-10.10.2003, Gasteig, München - Poster session - PG-07
PT Konferenz-Poster
AB
The accumulation of misfolded prion protein (PrPsc) in Scrapie is invariably associated with the activation of glia cells. Microglia are activated upon exposure to PrPsc and produce in response a variety of pro-inflammatory cytokines and chemokines. The subsequent astrocytosis is likely to be driven by microglia-secreted cytokines and chemokines.
Among the chemokines highly and very quickly upregulated during scrapie infections are CXCL9 and CXCL10, in the periphery known to be chemoattractants for T-cells. Scrapie is usually not associated with a pronounced migration of T or B cells into the CNS. CXCL9 and 10 bind to the CXC-receptor 3 (CXCR3), which is expressed on microglia, astrocytes and neurons.
To investigate the role of CXCR3 ligands in the pathogenesis of a neurodegenerative amyloidosis CXCR3-deficient (CXCR3-/-) mice were infected intracerebrally with the scrapie strain 139A and analysed in comparison to age matched wild-type controls with immunohistochemical and molecularbiological methods.
The CXCR3-/- mice showed a delayed disease onset and a significantly prolonged survival time. Immunohistochemistry revealed a strongly reduced activation of microglia cells in the terminal stage of the disease in comparison to wild-type mice. In contrast, immunohistochemistry for GFAP showed a major increase of the astrocytosis at the terminal stage in the CXCR3-/- mice. Both PET-blot and Western blot analysis determined a significantly increased accumulation of PrPsc at the asymptomatic stage of the disease in the CXCR3-/- mice in comparison with wild-type controls.
The results points toward an involvement of CXCR3 ligands (potentially CXCL9 and CXCL10) in glia activation and glia/neuronal interactions in the scrapie pathogenesis.
AD C. Riemer, J. Schultz, A. Schwarz, M. Burwinkel, T. Bamme, M. Baier, Robert Koch-Institute, Berlin, Germany; B. Lu, C. Gerard, Perlmutter Laboratory, Children's Hospital and Havard Medical School, Boston, USA
SP englisch
PO Deutschland