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The Journal of Neuroscience, November 8, 2006, 26(45):11753-11762; doi:10.1523/JNEUROSCI.2275-06.2006

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Neurobiology of Disease
Early and Rapid Engraftment of Bone Marrow-Derived Microglia in Scrapie

Josef Priller,^1,2 * Marco Prinz,^1,3 * Mathias Heikenwalder,^1 * Nicolas Zeller,¹ Petra Schwarz,¹ Frank L. Heppner,¹ and Adriano Aguzzi¹

¹Institute of Neuropathology, Department of Pathology, University of Zurich, 8091 Zurich, Switzerland, ²Departments of Psychiatry and Experimental Neurology, Charité-Universitätsmedizin Berlin, 10117 Berlin, Germany, and ³Institute of Neuropathology, University of Göttingen, 37075 Göttingen, Germany

Correspondence should be addressed to either of the following: Adriano Aguzzi, Institute of Neuropathology, University of Zurich, Schmelzbergstrasse 12, CH-8091 Zurich, Switzerland Email: adriano.aguzzi{at}usz.ch; or Josef Priller, Departments of Psychiatry and Experimental Neurology, Charité-Universitätsmedizin Berlin, 10117 Berlin, Germany Email: josef.priller{at}charite.de

Prion neuroinvasion is accompanied by maximal activation of microglia, the significance of which for pathogenesis is unknown. Here, we used bone marrow (BM) cells expressing GFP (green fluorescent protein) to study the turnover of microglia in mouse scrapie. We found that 50% of all brain microglia were replaced by BM-derived cells before clinical disease onset. In terminally sick mice, microglia density increased threefold to fourfold. Hence BM-derived microglia rapidly and efficaciously colonize the brain in scrapie. Whereas reconstitution of wild-type mice with prion protein-deficient (Prnp^o/o) BM did not alter scrapie pathogenesis, Prnp^o/o mice transplanted with wild-type BM cells were resistant to peripherally administered prions despite high levels of infectivity in the spleen. Cerebellar homogenates from prion-inoculated Prnp^o/o mice reconstituted with >10% of wild-type microglia failed to infect transgenic mice overexpressing the cellular prion protein. Hence, in contrast to previous reports, microglia are not competent for efficient prion transport and replication in vivo.

Key words: prion infectivity; microglia; bone marrow transplantation; green fluorescent protein; Purkinje cells; knock-out

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Received May 29, 2006; revised Sept. 26, 2006; accepted Sept. 27, 2006.

Correspondence should be addressed to either of the following: Adriano Aguzzi, Institute of Neuropathology, University of Zurich, Schmelzbergstrasse 12, CH-8091 Zurich, Switzerland Email: adriano.aguzzi{at}usz.ch; or Josef Priller, Departments of Psychiatry and Experimental Neurology, Charité-Universitätsmedizin Berlin, 10117 Berlin, Germany Email: josef.priller{at}charite.de

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