A zebrafish model of tauopathy allows in vivo imaging of neuronal cell death and drug evaluation
Dominik Paquet, … , Bettina Schmid, Christian Haass
Dominik Paquet, … , Bettina Schmid, Christian Haass
Published April 13, 2009
Citation Information: J Clin Invest. 2009;119(5):1382-1395. https://doi.org/10.1172/JCI37537.
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A zebrafish model of tauopathy allows in vivo imaging of neuronal cell death and drug evaluation

Abstract

Our aging society is confronted with a dramatic increase of patients suffering from tauopathies, which include Alzheimer disease and certain frontotemporal dementias. These disorders are characterized by typical neuropathological lesions including hyperphosphorylation and subsequent aggregation of TAU protein and neuronal cell death. Currently, no mechanism-based cures are available. We generated fluorescently labeled TAU transgenic zebrafish, which rapidly recapitulated key pathological features of tauopathies, including phosphorylation and conformational changes of human TAU protein, tangle formation, neuronal and behavioral disturbances, and cell death. Due to their optical transparency and small size, zebrafish larvae are well suited for both in vivo imaging and drug development. TAU-induced neuronal cell death was imaged by time-lapse microscopy in vivo. Furthermore, we used this zebrafish model to identify compounds targeting the TAU kinase glycogen synthase kinase 3β (GSK3β). We identified a newly developed highly active GSK3β inhibitor, AR-534, by rational drug design. AR-534 reduced TAU phosphorylation in TAU transgenic zebrafish. This transgenic zebrafish model may become a valuable tool for further studies of the neuropathology of dementia.

Authors

Dominik Paquet, Ratan Bhat, Astrid Sydow, Eva-Maria Mandelkow, Stefan Berg, Sven Hellberg, Johanna Fälting, Martin Distel, Reinhard W. Köster, Bettina Schmid, Christian Haass

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Figure 3

Rapid progression of AT8-positive late-stage FTD/AD-like pathology in transgenic embryos.

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Rapid progression of AT8-positive late-stage FTD/AD-like pathology in tr...
(A) Double whole-mount immunostainings for TAU phosphorylated at the AT8 epitope (a late marker of pathology) and the AT270 epitope (an early marker) together with staining by antibody K9JA, which shows expression of total TAU in 24-, 32-, and 48-hpf and 7-day-old transgenic zebrafish embryos. There are very few AT8-positive neurons in the spinal cord of 24-hour-old embryos, while this number increased significantly in 32-hour-old embryos and rose even further in 48-hour-old embryos. Finally, all TAU-expressing neurons contained the AT8 epitope in 7-day-old larvae. (B) In contrast, immunoreactivity of the early marker AT270 was already strong in many TAU-expressing cells at 24 hpf and became only slightly stronger at older stages. The level of total TAU detected in the same embryos by double staining with the K9JA antibody was similar between 24 hpf and 32 hpf. After 48 hours, a substantial part of TAU was transferred to the neuronal projections. In contrast, AT8-positive TAU remained mainly in the cell bodies. The AT8-positive somata combined with a lack of strongly AT8-positive neuronal projections is consistent with the pathological accumulation of modified TAU in neuronal cell bodies of patients. Lateral views of the trunk above the end of the yolk extension, anterior to the left. Scale bars: 50 μm.