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.

  • Source
    • "Embryos were treated with system water (RO water equilibrated with Instant Ocean salts - H2O) or 100 µM Lithium Chloride (LiCl) (Synth) [26] diluted in system water from 1 hour post-fertilization (hpf) until 5 days post-fertilization (dpf) (Figure 1A). Medium was daily replaced and controlled for pH. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Alzheimer's disease (AD) is a devastating neurodegenerative disorder with no effective treatment and commonly diagnosed only on late stages. Amyloid-β (Aβ) accumulation and exacerbated tau phosphorylation are molecular hallmarks of AD implicated in cognitive deficits and synaptic and neuronal loss. The Aβ and tau connection is beginning to be elucidated and attributed to interaction with different components of common signaling pathways. Recent evidences suggest that non-fibrillary Aβ forms bind to membrane receptors and modulate GSK-3β activity, which in turn phosphorylates the microtubule-associated tau protein leading to axonal disruption and toxic accumulation. Available AD animal models, ranging from rodent to invertebrates, significantly contributed to our current knowledge, but complementary platforms for mechanistic and candidate drug screenings remain critical for the identification of early stage biomarkers and potential disease-modifying therapies. Here we show that Aβ1-42 injection in the hindbrain ventricle of 24 hpf zebrafish embryos results in specific cognitive deficits and increased tau phosphorylation in GSK-3β target residues at 5dpf larvae. These effects are reversed by lithium incubation and not accompanied by apoptotic markers. We believe this may represent a straightforward platform useful to identification of cellular and molecular mechanisms of early stage AD-like symptoms and the effects of neuroactive molecules in pharmacological screenings.
    Full-text · Article · Sep 2014 · PLoS ONE
  • Source
    • "Transgenic zebrafish expressing human MAPT were generated and investigated prior to identification of the zebrafish ortholog(s) of MAPT. In these studies human MAPT was specifically expressed in zebrafish CNS neurons (Bai et al., 2007; Paquet et al., 2009). Bai et al. used the promoter of the enolase 2 gene to drive the expression of MAPT 4R in zebrafish neurons at approximately eightfold higher levels than what is observed in human brain. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Rodent models have been extensively used to investigate the cause and mechanisms behind Alzheimer's disease. Despite many years of intensive research using these models we still lack a detailed understanding of the molecular events that lead to neurodegeneration. Although zebrafish lack the complexity of advanced cognitive behaviors evident in rodent models they have proven to be a very informative model for the study of human diseases. In this review we give an overview of how the zebrafish has been used to study Alzheimer's disease. Zebrafish possess genes orthologous to those mutated in familial Alzheimer's disease and research using zebrafish has revealed unique characteristics of these genes that have been difficult to observe in rodent models. The zebrafish is becoming an increasingly popular model for the investigation of Alzheimer's disease and will complement studies using other models to help complete our understanding of this disease.
    Full-text · Article · Jun 2014 · Frontiers in Genetics
  • Source
    • "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). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Our ageing society is confronted with a dramatic increase in incidence of age-related neurodegenerative diseases; biomedical research leading to novel therapeutic strategies is crucial to address this problem. Animal models of neurodegenerative conditions are invaluable in improving our understanding of the molecular basis of pathology, potentially revealing novel targets for intervention. Here, we review transgenic animal models of Alzheimer’s and Parkinson’s disease reported in mice, zebrafish, Caenorhabditis elegans and Drosophila melanogaster. This information will enable researchers to compare different animal models targeting disease-associated molecules by genomic engineering and to facilitate the development of novel animal models for any particular study, depending on the ultimate research goals.
    Full-text · Article · Aug 2013 · Genes & genomics
Show more