Ein transgenes Zebrafischmodell zur Erforschung neurodegenerativer Erkrankungen am Beispiel der Tauopathien

Neurodegenerative dementias belong to the most common forms of neurological diseases, more than 25 million people are affected worldwide, among them 1 million in Germany. Currently, no mechanism-based treatments are available. Since age is the major risk factor for these dementias, the number of patients will double until 2050, due to the increasing life expectancies of people around the world. The neuropathology of Alzheimer’s disease, the most common form of dementia, is mainly characterized by the appearance of neurofibrillary tangles in neurons of the brain, as well as extracellular deposits of the Aβ peptide, called plaques. Tangles consist of filaments of a misfolded and posttranslationally modified form of the Tauprotein. Tangles are also a hallmark of other dementias, such as certain frontotemporal dementias. Dementias with Tau-pathology are therefore also termed Tauopathies. Current dementia research focuses on the questions, which degenerative processes take place early in the diseased neurons, why the cells die, and how this processed could be halted. Animal models are essential tools to study these aspects of neurodegenerative diseases. Researchers mainly use transgenic animals, in which a mutated human gene that accelerates the disease in humans was introduced. Due to the relatively late onset of symptoms in existing transgenic mouse models and the fact that it is not well feasible to use these animals for in vivo imaging of disease progression or large scale drug development, there is an unmet need for alternative animal models. Therefore, during the course of this project transgenic zebrafish were developed as a model of Tauopathies, which express a mutant form of the human Tau-protein and rapidly recapitulate major disease symptoms. Zebrafish are well suited for in vivo imaging due to the translucent body of the larvae. In addition, the small body size of the larvae allows performing large-scale drug development and in-vivo-validation approaches. In the Tau-transgenic zebrafish, the first pathologic alterations were visible after only a few hours: the human Tau-protein altered its folding and biochemical composition and was relocalized from neuronal projections to the cell body. Thereafter, first degenerative processes could be monitored, during which neurons died in the central nervous system of the transgenic fish. This neurodegeneration, which is typically associated with Tauopathies, could be monitored in vivo under the microscope for several hours. In addition, the transgenic animals formed neurofibrillary tangles after some weeks, another pathological hallmark of several dementias including Alzheimer’s disease. The results indicate that the Tau-transgenic animals recapitulate the most relevant symptoms of Tau-associated human dementias and therefore, the animals are well suited for Tauopathy research. Due to the rapidly occurring disease symptoms, the fish could also be used to test chemical compounds for their ability to modify disease symptoms. In this test, an inhibitor of the Tau-Kinase GSK3, which was newly developed by a pharmaceutical company, was able to highly reduce the pathologic alterations of the Tau protein. This inhibitor was more than twice as potent as previously published inhibitors. Interestingly, another chemically similar and in cell culture equally potent inhibitor was completely inactive in this in-vivo-test, presumably due to low uptake of the compound into the nervous system or rapid breakdown. This example shows the necessity for drug tests in living animals and the suitability of the fish system to rapidly perform these tests.

The experiments illustrate the usefulness of the new Tau-transgenic zebrafish to study early degenerative processes leading to neuronal death in dementias and also their abilities to identify new drug targets. As this is the first zebrafish model of Tau-associated dementias with disease symptoms worldwide, this work is an important contribution to current dementia research and drug identification approaches.