In findings that could lead to a new Alzheimer's disease drug, researchers at San Francisco Veterans Affairs Medical Center (SFVAMC) and University of California, San Francisco have isolated a protein fragment that nurtures brain cells, an effect that could prevent loss of brain function caused by the disease.
The fragment acts through the same mechanisms as its larger parent protein. However, a drug based on the fragment would be small enough to pass from the bloodstream into the brain, the researchers said.
These findings were presented today (November 8) in New Orleans at the 30th Annual meeting of the Society for Neuroscience, the world's largest neuroscience meeting.
The fragment is derived from a protein called Nerve Growth Factor (NGF), which maintains the health of many types of brain cells, including those damaged by Alzheimer's disease; it also helps strengthen the connections between cells.
But NGF can't be used as a treatment because the molecule is too large to get past the filtering mechanisms that protect the brain from bacteria and other agents in the blood that might damage it, said Frank Longo, MD, PhD, a UCSF professor and vice chair of neurology and SFVAMC chief of research.
Longo and his colleagues now have found that a much smaller portion of NGF may carry NGF's most useful functions.
"These studies offer the first demonstration that a small molecule mimicking a specific part of the NGF protein can activate the same key mechanisms in neurons that are activated by NGF, and in doing so prevent death of these neurons. Prior to this work, it was widely believed that the entire NGF protein was required to achieve its death-preventing activity," Longo said.
Other researchers had determined which sections of the NGF molecule dock to NGF receptors. Longo and his colleagues were hopeful that if they isolated these receptor-binding pieces, one of them might nurture nerve cells in the same way as the whole molecule.
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 vast chemical libraries for more potent compounds," he said. These chemical libraries contain thousands of drug-like chemicals that can be searched through computer databases.
"Without our active molecules to serve as guides, it would be quite difficult to effectively search these vast libraries," he said.
Chemicals that closely match the shapes and structures in the NGF fragments will be gathered for further testing in nerve cell cultures. The most potent of these will then be tested in mouse models of Alzheimer's disease, Longo said.
"Our lead compounds will contribute to the long-term goal of creating drugs that prevent the onset and/or slow the progression of Alzheimer's disease," he said.
Most of the results presented by Longo were also published in the September 22 issue of the Journal of Biological Chemistry. Co-authors on the study were Youmei Xie, MD, UCSF/SFVAMC postdoctoral researcher in neurology, Michelle Tisi, BA, lab technician, Tracy Yeo, PhD, UCSF assistant professor of neurology.
This research was supported by grants from the American Alzheimer's Association and the John Douglas French Foundation.
The Alzheimer's Association grant was managed by the Northern California Institute for Research and Education (NCIRE).
NCIRE is one of the fastest growing medical research groups in the nation. Founded in 1988, NCIRE now manages more than $20 million in funding from organizations such as the National Institutes of Health, the National Aeronautics and Space Administration, and the National Science Foundation. Based at the San Francisco VA Medical Center, NCIRE is the largest of the 86 congressionally authorized VA research corporations.