In a second experiment, the researchers wanted to more closely mimic the human clinical situation, so they waited for motor abnormalities to arise in the rats. At this stage many motor neurons were already lost, yet the VEGF treatment still provided benefits, prolonging the rats' lives slightly.
The researchers then tested whether more receptors for VEGF might give the neurons an advantage. They genetically engineered mice that had ALS and expressed the VEGF receptor in greater numbers than normal. "Overexpression of the VEGF receptor indeed protected against motor neuron degeneration," says Storkebaum. This result indicated that VEGF could act directly on motor neurons.
Next, they attempted to increase the supply of VEGF to neurons. Motor neurons, which are stricken by ALS, make physical contacts with muscle fiber cells. There, they release chemical messengers that tell the muscles to contract. This point of contact is called the neuromuscular junction.
They used a virus to deliver the gene for VEGF to muscle cells, resulting in increased expression of VEGF protein by the muscle cells. Once the virus was absorbed, the muscle cells started to produce VEGF, making it available to the neurons at the neuromuscular junctions. Once again, VEGF improved the disease course--the onset was later and the mice survived longer. The researchers also found more neuromuscular junctions, evidence that VEGF helps to preserve these crucial points of contact.
In future studies, the team hopes to determine whether the virus containing the VEGF gene can also be taken up by the nerve endings. If so, the neurons might transport the gene back to the cell body and produce VEGF in the spinal cord, where it could provide help to other neurons. Alternatively, the VEGF protein itself might be taken up by the neuron
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Contact: Leah Arinello
dawn@sfn.org
202-462-6688
Society for Neuroscience
24-Oct-2004