They tested one of these fragments, called loop 4, for its ability to maintain a culture of nerve cells growing in a dish. Like NGF itself, loop 4 helped neurons survive - twice as many cells survived after three days compared with an untreated culture. However, the fragment was only 40 percent as effective as the whole NGF protein in keeping nerve cells alive. Although this may seem like a small percentage, Longo said this is a good lead to follow in developing a more effective molecule.
Nerves treated with the NGF fragment also perform another of NGF's functions - they stimulated the growth of new axons, the fibers that deliver signals from one nerve cell to another, Longo said.
Other evidence from the study supports the idea that this fragment is acting on neurons in the same way as NGF. Looking within the nerve cell, Longo and his colleagues found that two chemical pathways in nerve cells that are switched on by NGF, are also activated in cells treated with the loop 4 fragment. They also showed that molecules that blocked the NGF receptor could prevented the NGF fragment from promoting cell growth and survival.
"These NGF fragments act via mechanisms analogous to NGF protein and can therefore be used as a guide for identifying even more potent compounds with properties suitable for pharmaceutical development," Longo said.
A few years ago, Longo's group published studies of another NGF fragment, loop 1, which binds to a different part of the NGF receptor. While loop 1 was not as effective at nurturing nerve cells as loop 4, Longo plans to use both of the fragments as leads to more effective molecules.
The next step in developing these fragments into drugs that might slow Alzheimer's, Longo said, will be to search for molecules that contain the loop 4 structure, but that also have features that might make them more effective. "We will use the shapes and structures of our small designer fragments to search
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Contact: Kevin Boyd
kboyd@pubaff.ucsf.edu
415-476-2557
University of California - San Francisco
7-Nov-2000