In the last 40 years, the pathogenesis of transmissible spongiform encephalopathies of humans and animals have been the subject of exciting discoveries and also of passionate controversies. Although the human forms of these diseases are rare, the recent epidemics of bovine spongiform encephalopathy has most dramatically raised the issue of the transmissibility from affected animals to humans. This review summarizes some current hypotheses on the nature of the infectious agent causing these diseases, and on the pathogenetic pathways which produce histologically detectable damage to the central nervous system. The main focus is on the use of transgenic and knockout mice which, combined with organ transplantation and bone marrow reconstitution techniques, have provided powerful tools for dissecting the pathogenesis of these diseases.

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