First observation of neuron death in living being enables development of Alzherimer's drugs

MUNICH, GERMANY--Current methods of studying nerve cells affected by Alzheimer's disease are limited to post-mortem animal models and complicated methods. A new approach, developed at the Center for Neurodegenerative Disease at Ludwig-Maximilians-Universitaet (LMU) has enabled the first directly observed imaging of neuron death in a living organism. The approach, which involves a laser microscope and fluorescent protein, promises to aid development of therapies.

A team of scientists headed by Professor Christian Haass inserted into live zebrafish larvae a human gene that leads to a severe form of Alzheimer's in humans. The translucent larvae then developed characteristic symptoms, including deposits in nerve cells and the selective loss of neurons. "Our discovery now allows us to perform a targeted search for drugs that can stop the extensive cell death, and thereby stop dementia in patients," says Haass. "The first findings have already shown that we can in principle use drugs to block at least some of the disease-related processes in the zebrafish."

Haass and his two colleagues, Dr. Bettina Schmidt and Dominik Paquet of the Deutsche Zentrum für Neurodegenerative Erkrankungen, DZNE (German Center for Neurodegenerative Disease) at LMU Muenchen and the cluster of excellence Center for Integrated Protein Science (CIPSM), conducted the research. Paquet, lead author of a new report in the Journal of Clinical Investigation detailing the research, told BioOptics World that they used a Zeiss LSM 510 Meta confocal microscope to make the observation, and that they anesthetized the fish and imaged them every 3 minutes for about 12 hours. "The fish produce the fluorescent protein DsRed in their neurons together with the Alzheimer's disease-associated protein Tau," Paquet said. "In addition, we have incubated the fish in a low amount of acridine orange, which is a chemical compound that stains nucleic acids, but does preferentially enter dying cells in our fish, because the plasma membrane of these cell is breaking down."

This method allowed the researchers to directly watch the neurons as they died. This way, "it should also be possible to watch and test directly whether potential drugs actually do have a protective action," Haass said. "First experiments using newly developed drugs have already confirmed this: One drug did have an effect in the living fish--and was able to block the disease-related processes in the zebrafish at least to some extent."

The work has already been praised by those in the field: On March 16, Paquet, a PhD student at Haass' lab, was honored with the Verum Award 2009 and the Leda Hanin Award at the International Conference on Alzheimer's and Parkinson's Diseases in Prague. Both distinctions are awarded to outstanding young researchers and are each coming with 2000 euros. (CIPSM/suwe and SFB 596)

Approximately 12 to 18 million patients around the world suffer from Alzheimer's disease, and the trend is increasing. The search for causal therapies is sorely needed, and devastation of neurons can only be truly confirmed after the death of the patient. Even in animal models, the destruction of nerve cells has only been observable to a very limited extent and with great difficulty.

For more information on the work, please see the paper, A zebrafish model of tauopathy allows in vivo imaging of neuronal cell death and drug evaluation, in the Journal of Clinical Investigation. See also the website for Prof. Haass's lab.

Posted by Barbara G. Goode,, for BioOptics World.

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