SFVAMC/UCSF researchers develop lead for a new Alzheimer's disease drug -- a fragment of a brain gro

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.