Optical imaging detects apoptosis in the brain and peripheral organs of prion-infected mice

Abstract

Activation of the caspase family of cysteine proteases is proposed tobe 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 prionsby 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 waslocalized 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. © 2011 by the American Association of Neuropathologists, Inc.