A zebrafish model of tauopathy allows in vivo imaging of neuronal cell death and drug evaluation. J Clin Invest

Deutsches Zentrum für Neurodegenerative Erkrankungen, Munich, Germany.
The Journal of clinical investigation (Impact Factor: 13.22). 05/2009; 119(5):1382-95. DOI: 10.1172/JCI37537
Source: PubMed


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 3beta (GSK3beta). We identified a newly developed highly active GSK3beta 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.

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Article: A zebrafish model of tauopathy allows in vivo imaging of neuronal cell death and drug evaluation. J Clin Invest

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    • "Early pathology signs include disease-specific hyperphosphorylation and conformational changes of TAU in addition to neuronal and behavioral abnormalities. Using this transgenic line, GSK3b inhibitors have been screened for drugs that inhibit phosphorylation of human TAU (Paquet et al. 2009). Caenorhabditis elegans has a single TAU ortholog, ptl-1 that is expressed in many cells including mechanosensory neurons of the body; loss of ptl-1 decreases the number of viable progeny and these animals are slightly less sensitive to body touch (Goedert et al. 1996; McDermott et al. 1996; Gordon et al. 2008). "
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