Experimental Bovine Spongiform Encephalopathy in Squirrel Monkeys: The Same Complex Proteinopathy Appearing after Very Different Incubation Times
Pedro Piccardo,
Juraj Cervenak,
Wilfred Goldmann,
Paula Stewart,
Kitty L. Pomeroy,
Luisa Gregori,
Oksana Yakovleva,
David M. Asher
Affiliations
Pedro Piccardo
Laboratory of Bacterial and Transmissible Spongiform Encephalopathy Agents, Division of Emerging and Transfusion-Transmitted Diseases, Office of Blood Research and Review, Center for Biologics Evaluation and Research, United States Food and Drug Administration, Silver Spring, MD 20993, USA
Juraj Cervenak
Laboratory of Bacterial and Transmissible Spongiform Encephalopathy Agents, Division of Emerging and Transfusion-Transmitted Diseases, Office of Blood Research and Review, Center for Biologics Evaluation and Research, United States Food and Drug Administration, Silver Spring, MD 20993, USA
Wilfred Goldmann
The Roslin Institute, University of Edinburgh, Midlothian EH25 9RG, UK
Paula Stewart
The Roslin Institute, University of Edinburgh, Midlothian EH25 9RG, UK
Kitty L. Pomeroy
Laboratory of Bacterial and Transmissible Spongiform Encephalopathy Agents, Division of Emerging and Transfusion-Transmitted Diseases, Office of Blood Research and Review, Center for Biologics Evaluation and Research, United States Food and Drug Administration, Silver Spring, MD 20993, USA
Luisa Gregori
Laboratory of Bacterial and Transmissible Spongiform Encephalopathy Agents, Division of Emerging and Transfusion-Transmitted Diseases, Office of Blood Research and Review, Center for Biologics Evaluation and Research, United States Food and Drug Administration, Silver Spring, MD 20993, USA
Oksana Yakovleva
Laboratory of Bacterial and Transmissible Spongiform Encephalopathy Agents, Division of Emerging and Transfusion-Transmitted Diseases, Office of Blood Research and Review, Center for Biologics Evaluation and Research, United States Food and Drug Administration, Silver Spring, MD 20993, USA
David M. Asher
Laboratory of Bacterial and Transmissible Spongiform Encephalopathy Agents, Division of Emerging and Transfusion-Transmitted Diseases, Office of Blood Research and Review, Center for Biologics Evaluation and Research, United States Food and Drug Administration, Silver Spring, MD 20993, USA
Incubation periods in humans infected with transmissible spongiform encephalopathy (TSE) agents can exceed 50 years. In humans infected with bovine spongiform encephalopathy (BSE) agents, the effects of a “species barrier,” often observed when TSE infections are transmitted from one species to another, would be expected to increase incubation periods compared with transmissions of same infectious agents within the same species. As part of a long-term study investigating the susceptibility to BSE of cell cultures used to produce vaccines, we inoculated squirrel monkeys (Saimiri sp., here designated SQ) with serial dilutions of a bovine brain suspension containing the BSE agent and monitored them for as long as ten years. Previously, we showed that SQ infected with the original “classical” BSE agent (SQ-BSE) developed a neurological disease resembling that seen in humans with variant CJD (vCJD). Here, we report the final characterization of the SQ-BSE model. We observed an unexpectedly marked difference in incubation times between two animals inoculated with the same dilution and volume of the same C-BSE bovine brain extract on the same day. SQ-BSE developed, in addition to spongiform changes and astrogliosis typical of TSEs, a complex proteinopathy with severe accumulations of protease-resistant prion protein (PrPTSE), hyperphosphorylated tau (p-tau), ubiquitin, and α-synuclein, but without any amyloid plaques or β-amyloid protein (Aβ) typical of Alzheimer’s disease. These results suggest that PrPTSE enhanced the accumulation of several key proteins characteristically seen in human neurodegenerative diseases. The marked variation in incubation periods in the same experimental TSE should be taken into account when modeling the epidemiology of human TSEs.
