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Near-infrared fluorescence imaging of apoptotic neuronal cell death in a live animal model of prion disease.

ABSTRACT: Apoptotic cell death via activation of the caspase family of cysteine proteases is a common feature of many neurodegenerative diseases including Creutzfeldt-Jakob disease. Molecular imaging of cysteine protease activities at the preclinical stage may provide valuable mechanistic information about pathophysiological pathways involved in disease evolution and in response to therapy. In this study, we report synthesis and characterization of a near-infrared (NIR) fluorescent contrast agent capable of noninvasively imaging neuronal apoptosis in vivo, by conjugating a NIR cyanine dye to Val-Ala-Asp-fluoromethylketone (VAD-fmk), a general inhibitor of active caspases. Following intravenous administration of the NIR-VAD-fmk contrast agent, in vivo fluorescence reflectance imaging identified significantly higher levels of active caspases in the brain of mice with advanced but preclinical prion disease, when compared with healthy controls. The contrast agent and related analogues will enable the longitudinal study of disease progression and therapy in animal models of many neurodegenerative conditions.

SUBMITTER: Lawson VA

PROVIDER: S-EPMC3368636 | biostudies-literature | 2010 Nov

REPOSITORIES: biostudies-literature

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Near-infrared fluorescence imaging of apoptotic neuronal cell death in a live animal model of prion disease.

Lawson Victoria A VA Haigh Cathryn L CL Roberts Blaine B Kenche Vijaya B VB Klemm Helen M J HM Masters Colin L CL Collins Steven J SJ Barnham Kevin J KJ Drew Simon C SC

ACS chemical neuroscience 20100930 11

Apoptotic cell death via activation of the caspase family of cysteine proteases is a common feature of many neurodegenerative diseases including Creutzfeldt-Jakob disease. Molecular imaging of cysteine protease activities at the preclinical stage may provide valuable mechanistic information about pathophysiological pathways involved in disease evolution and in response to therapy. In this study, we report synthesis and characterization of a near-infrared (NIR) fluorescent contrast agent capable ...[more]

PMID: 22778809

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Project description:PURPOSE:Near-infrared fluorescence (NIRF) imaging has been widely used in preclinical studies; however, its low tissue penetration represents a daunting problem for translational clinical imaging of neurodegenerative diseases. The retina is known as an extension of the central nerve system (CNS), and it is widely considered as a window to the brain. Therefore, the retina can be considered as an alternative organ for investigating neurodegenerative diseases, and an eye represents an ideal NIRF imaging organ, due to its minimal opacity. PROCEDURES:NIRF ocular imaging (NIRFOI), for the first time, was explored for imaging of Alzheimer's disease (AD) via utilizing "smart" fluorescent probes CRANAD-X (X = - 2, - 3, - 30, - 58, and - 102) for amyloid beta (Aβ), and CRANAD-61 for reactive oxygen species (ROS). Mice were intravenously injected the fluorescence dyes and images from the eyes were captured with an IVIS imaging system at different time points. RESULTS:All of the tested NIRF probes could be used to differentiate transgenic AD mice and WT mice, and NIRFOI could provide much higher sensitivity for imaging Aβs than NIRF brain imaging did. Our data suggested that NIRFOI could capture the imaging signals from both soluble and insoluble Aβ species. Moreover, we demonstrated that NIRFOI with CRANAD-102 could be used to monitor the therapeutic effects of BACE-1 inhibitor LY2811376. Compared to NIRF brain imaging, NIRFOI provided a larger change of Aβ levels before and after LY2811376 treatment. In addition, we demonstrated that CRANAD-61 could be used to image reactive oxygen species in the eyes. CONCLUSION:The large detection margin by NIRFOI is very important for both diagnosis and therapy response monitoring. Compared to fluorescence microscopic imaging, NIRFOI captures signals with a wide angle (large field of view (FOV)) and can be used to detect soluble Aβs. We believe that NIRFOI has remarkable translational potential for future human studies and can be a potential imaging technology for fast, cheap, accessible, and reliable screening of AD in the future.

Dataset Information

Near-infrared fluorescence imaging of apoptotic neuronal cell death in a live animal model of prion disease.

Publications

Near-infrared fluorescence imaging of apoptotic neuronal cell death in a live animal model of prion disease.

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