PUBLICATION
A zebrafish model of tauopathy allows in vivo imaging of neuronal cell death and drug evaluation
- Authors
- Paquet, D., Bhat, R., Sydow, A., Mandelkow, E.M., Berg, S., Hellberg, S., Fälting, J., Distel, M., Köster, R.W., Schmid, B., and Haass, C.
- ID
- ZDB-PUB-090417-2
- Date
- 2009
- Source
- J. Clin. Invest. 119(5): 1382-1395 (Journal)
- Registered Authors
- Distel, Martin, Haass, Christian, Köster, Reinhard W., Paquet, Dominik, Schmid, Bettina
- Keywords
- none
- MeSH Terms
-
- Drug Evaluation, Preclinical/methods*
- Luminescent Proteins/genetics
- Luminescent Proteins/metabolism
- Escape Reaction
- Protein Conformation
- Enzyme Inhibitors/chemistry
- Enzyme Inhibitors/pharmacokinetics
- Enzyme Inhibitors/pharmacology
- Synaptotagmins/metabolism
- Motor Neurons/drug effects
- Motor Neurons/metabolism
- Motor Neurons/pathology
- Glycogen Synthase Kinase 3/antagonists & inhibitors
- Glycogen Synthase Kinase 3/chemistry
- Glycogen Synthase Kinase 3/genetics
- Neurons/drug effects
- Neurons/metabolism
- Neurons/pathology*
- Disease Models, Animal*
- Drug Design
- Sequence Alignment
- Tauopathies/drug therapy*
- Tauopathies/metabolism
- Tauopathies/pathology*
- Animals
- Embryo, Nonmammalian/abnormalities
- Embryo, Nonmammalian/drug effects
- Embryo, Nonmammalian/metabolism
- Embryo, Nonmammalian/pathology
- Phosphorylation/drug effects
- tau Proteins/genetics
- tau Proteins/metabolism
- Animals, Genetically Modified
- Larva/anatomy & histology
- Larva/drug effects
- Larva/metabolism
- Molecular Structure
- Zebrafish*/genetics
- Humans
- Models, Molecular
- Cell Death
- Spinal Cord/metabolism
- Spinal Cord/pathology
- PubMed
- 19363289 Full text @ J. Clin. Invest.
Citation
Paquet, D., Bhat, R., Sydow, A., Mandelkow, E.M., Berg, S., Hellberg, S., Fälting, J., Distel, M., Köster, R.W., Schmid, B., and Haass, C. (2009) A zebrafish model of tauopathy allows in vivo imaging of neuronal cell death and drug evaluation. J. Clin. Invest.. 119(5):1382-1395.
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 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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping