In Alzheimer's disease, as well as in other neurodegenerative disorders, a protein normally present in our cells forms abnormal “tangles” in our brain.
When scientists have looked at the tangles in detail they have found that this protein (called tau) has been modified by the attachment of many phosphate radicals to its surface.
It has, however, remained unclear whether this modification plays any role in the creation of the tangles and the accompanying neurodegeneration, or is merely an effect of the degeneration.
Now, a research team at the Neurogenetics Program, Department of Neurology, University of California Los Angeles School of Medicine, led by Daniel Geschwind has addressed these questions by generating transgenic flies that produce human tau in their eyes.
Their findings are reported in today's issue of Neuron.
First, Geschwind and colleagues examined the eyes of the transgenic flies in detail. They noticed that their neurons developed abnormally and displayed progressive degeneration. However, the tau-containing tangles characteristic of Alzheimer's disease were not apparent.
Next, the researchers assessed the effect of other proteins on the tau-induced neurodegeneration. Strikingly, several members of the “wingless pathway” (a group of proteins identified for their involvement in setting out the body plan of both flies and humans) were able to modify the degeneration.
Specifically, Geschwind and colleagues were able to show that over-expression of one of these members, which is known to directly attach phosphates to human tau, led to accelerated neurodegeneration and the appearance of tangle-like structures.
As Geschwind points out, these findings suggest that there is indeed a causal relationship between tau modification and neurodegeneration. In addition, they identify a group of molecules that can modulate this degeneration, which may have an impact on the development of future therapies.
In this regard, the fly model (which for the first time displays the abnormal tangles and filaments observed in Alzheimer's patients) should be an invaluable tool.
[Contact: Daniel H. Geschwind ]