Prof Adriano Aguzzi • Chairman, Department of Pathology, Zurich • Director, Institute of Neuropathology, Zurich • Director, Swiss National Reference Center for Prion diseases

Background

In 1992, Charles Weissmann asked me to collaborate with him and Hansruedi Büeler on the characterization of mice deficient in the normal prion protein. These mice turned out to be resistant to prions (1). I then turned my interest to the mechanism by which prions damage brain cells, and found that expression of the normal prion protein by neurons is necessary for the development of histological damage (2). My lab showed that "neuroinvasion", i.e. the process by which prions march through the body of the host towards the brain, relies on expression of the normal prion protein in a non-hematopoietic extracerebral site (3). We then developed the hypothesis that neuroinvasion takes place in distinct steps: first the epithelial is trespassed (4), then the lymphoreticular system is colonized. Finally infectivity progresses from lymphoreticular organs to the central nervous system (5) via sympathetic nerves (6, 7). We are now testing the role of microglia using a conditional microglial paralysis model (8).

We set out to identify the lymphoreticular compartments responsible for the spread of prions. B-lymphocytes are required for peripheral prion pathogenesis (9), although the presence of the normal prion protein on B-lymphocytes is not necessary for this process (10). With Charles Weissmann, we found that one mechanism of action of B cells consists of presentation of lymphotoxins to follicular dendritic cells(FDCs) (11). This finding may pave the way to post-exposure prophylaxis (12) exploiting the anti-prion effect of soluble lymphotoxin-ß receptors. The distance between FDCs and splenic nerves was found to determine the velocity of neuroinvasion (13). Markus Glatzel and I also found PrPSc also in lymphoid organs of patients with Creutzfeldt-Jakob disease (14), suggesting similar pathogenetic mechanisms in humans and in our mouse models. As B-cells home to inflamed organs, we tested whether inflammation specifies the organ tropism of prions. This prediction proved correct (15).

But why do follicular dendritic cells accumulate prions? We tested whether prion uptake may be complement-mediated. Indeed, certain components of the complement system proved to play an important role in pathogenesis (16). Progress in the understanding of pathogenesis and a elucidation of possible therapeutical and prophylactic approaches, such as immunotherapy (17) must go hand-in-hand with diagnostic procedures. With this in mind, we initiated a screen for plasma proteins that bind specifically disease-associated prion protein (18, 19). In addition, we found that soluble dimeric prion protein binds selectively PrPSc (20). This may be exploitable as the basis of a sensitive diagnostic assay, possibly for BSE and for human prion diseases.

Selected Publications (discussed above)

1. Büeler, H.R., Aguzzi, A., Sailer, A., Greiner, R.A., Autenried, P., Aguet, M., and Weissmann, C. 1993.
Mice devoid of PrP are resistant to scrapie. Cell 73:1339-1347.

2. Brandner, S., Isenmann, S., Raeber, A., Fischer, M., Sailer, A., Kobayashi, Y., Marino, S., Weissmann, C., and Aguzzi, A. 1996.
Normal host prion protein necessary for scrapie-induced neurotoxicity. Nature 379:339-343.

3. Blättler, T., Brandner, S., Raeber, A.J., Klein, M.A., Voigtländer, T., Weissmann, C., and Aguzzi, A. 1997.
PrP-expressing tissue required for transfer of scrapie infectivity from spleen to brain. Nature 389:69-73.

4. Heppner, F.L., Christ, A.D., Klein, M.A., Prinz, M., Fried, M., Kraehenbuhl, J.P., and Aguzzi, A. 2001.
Transepithelial prion transport by M cells. Nat Med 7:976-977.

5. Aguzzi, A., and Weissmann, C. 1997.
Prion research: the next frontiers. Nature 389:795-798.

6. Glatzel, M., Flechsig, E., Navarro, B., Klein, M.A., Paterna, J.C., Bueler, H., and Aguzzi, A. 2000.
Adenoviral and adeno-associated viral transfer of genes to the peripheral nervous system. Proc Natl Acad Sci USA 97:442-447.

7. Glatzel, M., Heppner, F.L., Albers, K.M., and Aguzzi, A. 2001.
Sympathetic innervation of lymphoreticular organs is rate limiting for prion neuroinvasion. Neuron 31:25-34.

8. Heppner, F.L., Greter, M., Marino, D., Falsig, J., Raivich, G., Hovelmeyer, N., Waisman, A., Rulicke, T., Prinz, M., Priller, J., et al. 2005.
Experimental autoimmune encephalomyelitis repressed by microglial paralysis. Nat Med 11:146-152.

9. Klein, M.A., Frigg, R., Flechsig, E., Raeber, A.J., Kalinke, U., Bluethmann, H., Bootz, F., Suter, M., Zinkernagel, R.M., and Aguzzi, A. 1997.
A crucial role for B cells in neuroinvasive scrapie. Nature 390:687-690.

10. Klein, M.A., Frigg, R., Raeber, A.J., Flechsig, E., Hegyi, I., Zinkernagel, R.M., Weissmann, C., and Aguzzi, A. 1998.
PrP expression in B lymphocytes is not required for prion neuroinvasion. Nat Med 4:1429-1433.

11. Montrasio, F., Frigg, R., Glatzel, M., Klein, M.A., Mackay, F., Aguzzi, A., and Weissmann, C. 2000.
Impaired prion replication in spleens of mice lacking functional follicular dendritic cells. Science 288:1257-1259.

12. Aguzzi, A., and Collinge, J. 1997.
Post-exposure prophylaxis after accidental prion inoculation. Lancet 350:1519-1520.

13. Prinz, M., Heikenwalder, M., Junt, T., Schwarz, P., Glatzel, M., Heppner, F.L., Fu, Y.X., Lipp, M., and Aguzzi, A. 2003.
Positioning of follicular dendritic cells within the spleen controls prion neuroinvasion. Nature 425:957-962.

14. Glatzel, M., Abela, E., Maissen, M., and Aguzzi, A. 2003. Extraneural pathologic prion protein in sporadic Creutzfeldt-Jakob disease.
N Engl J Med 349:1812-1820.

15. Heikenwalder, M., Zeller, N., Seeger, H., Prinz, M., Klohn, P.C., Schwarz, P., Ruddle, N.H., Weissmann, C., and Aguzzi, A. 2005.
Chronic lymphocytic inflammation specifies the organ tropism of prions. Science 307:1107-1110.

16. Klein, M.A., Kaeser, P.S., Schwarz, P., Weyd, H., Xenarios, I., Zinkernagel, R.M., Carroll, M.C., Verbeek, J.S., Botto, M., Walport, M.J., et al. 2001.
Complement facilitates early prion pathogenesis. Nat Med 7:488-492.

17. Heppner, F.L., Musahl, C., Arrighi, I., Klein, M.A., Rulicke, T., Oesch, B., Zinkernagel, R.M., Kalinke, U., and Aguzzi, A. 2001.
Prevention of Scrapie Pathogenesis by Transgenic Expression of Anti-Prion Protein Antibodies. Science 294:178-182.

18. Fischer, M.B., Roeckl, C., Parizek, P., Schwarz, H.P., and Aguzzi, A. 2000.
Binding of disease-associated prion protein to plasminogen. Nature 408:479-483.

19. Maissen, M., Roeckl, C., Glatzel, M., Goldmann, W., and Aguzzi, A. 2001.
Plasminogen binds to disease-associated prion protein of multiple species. Lancet 357:2026-2028.

20. Meier, P., Genoud, N., Prinz, M., Maissen, M., Rulicke, T., Zurbriggen, A., Raeber, A.J., and Aguzzi, A. 2003.
Soluble dimeric prion protein binds PrP(Sc) in vivo and antagonizes prion disease. Cell 113:49-60.

For an up-to-date publication list please click here .