A zebrafish model of tauopathy allows in vivo imaging of neuronal cell death and drug evaluation
J Clin Invest. 2009 May;119(5):1382-95. doi: 10.1172/JCI37537. Epub 2009 Apr 13.
| Authors/Editors: |
Paquet D Bhat R Sydow A Mandelkow EM Berg S Hellberg S Fälting J Distel M Köster RW Schmid B Haass C |
|---|---|
| Publication Date: | 2009 |
| Type of Publication: | Journal Article |
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.
