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 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 (PrP Sc). 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, PrP and spongiform changes.

Cytosolic caspases mediate mislocalised SOD2 depletion in an in vitro model of chronic prion infection

“…Evidence of caspase activation has been detected in brain tissue obtained post-mortem from human Creutzfeldt-Jakob disease (CJD) patients (Jesionek-Kupnicka et al, 1997; Puig and Ferrer, 2001) and can be observed in the brains of live mice in the pre-terminal phases of prion disease (Lawson et al, 2010), with caspase-reactive aggregates observed inside neurons using the same active caspase label as in the current study (Drew et al, 2011). Furthermore, in GT1 and N2a cell models of prion infection, aggresomes associated with increased caspases 3 and 8 activity are formed when the proteosome is inhibited (Kristiansen et al, 2005).…”

Synaptic Dysfunction in Prion Diseases: A Trafficking Problem?

“…Analysis of brains from scrapie-affected sheep, CJD and FFI patients, and experimentally prion-infected rodents identified cells with fragmented nuclei, DNA cleavage, and caspase activation, confirming the involvement of PCD [31–45]. In addition, transgenic Tg(PG14) mice expressing a mutant PrP carrying a nine-octapeptide repeat insertion associated with a genetic prion disease showed massive apoptosis of cerebellar granule neurons (CGNs) [46].…”

A Molecular Imaging Primer: Modalities, Imaging Agents, and Applications

“…Peptide imaging agents can be used to visualize a range of targets, including integrins (20,57,294), matrix metalloproteinases (36,187), caspases (91,95), somatostatin receptors (82,136,331), neuropeptide Y receptor (253,485), and gastrin releasing peptide receptor (372,427,428). See TABLE 2 for some specific examples of peptide molecular imaging agents that can be used for optical, PET, and SPECT imaging.…”