The contribution of microglia to scrapie pathogenesis

Completed Research Project

Summary / Zusammenfassung: The identification of mediators of pathogenesis and neurotoxicity in transmissible spongiform encephalopathies (TSEs) remains a crucial issue to be addressed. Therefore, this project aims to clarify the contribution of activated microglial cells, the brain’s intrinsic immunocompetent macrophages, on scrapie pathogenesis (Heppner et al., 2001b). We designed a transgenic mouse model for conditional depletion of microglial cells. The transgene consists of the coding region for the herpes simplex virus-thymidine kinase (HSV-tk) under the control of the macrophage-specific CD11b-promoter. HSV-tk is a widely used suicide gene that converts antiviral nucleotide analog prodrugs such as ganciclovir (GCV) to a monophosphorylated form, which is then transformed into a toxic triphosphate by endogenous cellular kinases. By reconstituting CD11b-HSV-tk mice with bone marrow derived from wild-type mice, transgenic expression of the HSV-tk will be restricted to microglial cells, thus rendering them sensitive to GCV. The biological function of microglia in scrapie pathogenesis as well as in other CNS diseases such as experimental allergic encephalomyelitis (EAE) will be investigated.

Publications / Publikationen: Heppner, F. L., Prinz, M., and Aguzzi, A. (2001b). Pathogenesis of prion diseases: possible implications of microglial cells. Prog Brain Res 132, 737-750.

Keywords / Suchbegriffe: Microglia, prion disease, transgenic, HSV-tk, CD11b

Project Leadership and Contacts / Projektleitung und Kontakte

Frank L. Heppner (Project Leader)	frank.heppner@usz.ch
Prof. A. Aguzzi	adriano@pathol.uzh.ch

Other Links to external Webpages: http://www.uzh.ch/pathol/neuropathologie/d/index.html

Funding Source(s) / Unterstützt durch: Foundation, Others
HFSP, Stammbach-Stiftung, Bonizzi-Theler-Stiftung

In Collaboration with / In Zusammenarbeit mit

Burkhard Becher, Neuroinflammatory Unit, USZ Zurich	Switzerland
Ari Waisman, Laboratory for Molecular Immunology, University Cologne Martin Zenke, MDC Berlin	Germany
Genadij Raivich, Perinatal Brain Repair Group, UCL London	United Kingdom