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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Animals, Genetically Modified
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Cell Death
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Disease Models, Animal*
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Drug Design
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Drug Evaluation, Preclinical / methods*
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Embryo, Nonmammalian / abnormalities
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Embryo, Nonmammalian / drug effects
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Embryo, Nonmammalian / metabolism
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Embryo, Nonmammalian / pathology
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Enzyme Inhibitors / chemistry
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Enzyme Inhibitors / pharmacokinetics
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Enzyme Inhibitors / pharmacology
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Escape Reaction
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Glycogen Synthase Kinase 3 / antagonists & inhibitors
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Glycogen Synthase Kinase 3 / chemistry
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Glycogen Synthase Kinase 3 / genetics
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Glycogen Synthase Kinase 3 beta
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Humans
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Larva / anatomy & histology
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Larva / drug effects
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Larva / metabolism
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Luminescent Proteins / genetics
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Luminescent Proteins / metabolism
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Models, Molecular
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Molecular Structure
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Motor Neurons / drug effects
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Motor Neurons / metabolism
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Motor Neurons / pathology
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Neurons / drug effects
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Neurons / metabolism
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Neurons / pathology*
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Phosphorylation / drug effects
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Protein Conformation
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Red Fluorescent Protein
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Sequence Alignment
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Spinal Cord / metabolism
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Spinal Cord / pathology
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Synaptotagmins / metabolism
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Tauopathies / drug therapy*
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Tauopathies / metabolism
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Tauopathies / pathology*
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Zebrafish* / genetics
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tau Proteins / genetics
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tau Proteins / metabolism
Substances
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Enzyme Inhibitors
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Luminescent Proteins
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MAPT protein, human
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tau Proteins
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Synaptotagmins
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GSK3B protein, human
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Glycogen Synthase Kinase 3 beta
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Glycogen Synthase Kinase 3