Journal
JOURNAL OF NEUROPATHOLOGY AND EXPERIMENTAL NEUROLOGY
Volume 70, Issue 2, Pages 143-150Publisher
OXFORD UNIV PRESS INC
DOI: 10.1097/NEN.0b013e3182084a8c
Keywords
Apoptosis; Caspase; Fluorescence; Mice; Optical imaging; Prion
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Funding
- VCF-George Perry Fund
- Arthur and Mary Osborn Charitable Trust
- William Buckland Foundation
- University of Melbourne
- NHMRC [400183]
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Activation of the caspase family of cysteine proteases is proposed to be an important cell death mechanism in transmissible spongiform encephalopathies or prion diseases. We determined the extent of caspase activation in the brain and peripheral organs of mice that showed clinical signs after intracerebral inoculation with mouse-adapted prions by in vivo administration of a red fluorescent pan-caspase inhibitor, sulforhodamine B-Val-Ala-Asp(OMe)-fluoromethylketone. Fluorescence reflectance imaging identified a significant increase in active caspases in brains of prion-infected, but not uninfected, mice that correlated with increases in procaspase-3 and cleaved caspase-3, a central effector caspase, assessed by Western immunoblot analysis. Fluorescence was found in brain regions in which neuronal loss occurs; immunohistochemical analysis indicated that fluorescence was localized within and adjacent to deposits of abnormal disease-associated conformers of the prion protein (PrPSc). Fluorescence was also significantly increased in the kidney, lung, and ileum of prion-infected mice. This premortem labeling of caspase activation in the brain, and importantly in peripheral organs, could be exploited as a biomarker for longitudinal monitoring of prion disease progression and the impact of therapy in vivo in addition to, or independently of, PrPSc and spongiform changes.
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