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Jan.
20, 2005 — Brain cells in a mouse model of Alzheimer's
disease have surprised scientists with their ability
to recuperate after the disorder's characteristic brain
plaques are removed.
Researchers
at Washington University School of Medicine in St. Louis
injected mice with an antibody for a key component of
brain plaques, the amyloid beta (Abeta) peptide. In
areas of the brain where antibodies cleared plaques,
many of the swellings previously observed on nerve cell
branches rapidly disappeared.
"These
swellings represent structural damage that seemed to
be well established and stable, but clearing out the
plaques often led to rapid recovery of normal structure
over a few days," says senior author David H. Holtzman,
M.D., the Charlotte and Paul Hagemann Professor and
head of the Department of Neurology. "This provides
confirmation of the potential benefits of plaque-clearing
treatments and also gets us rethinking our theories
on how plaques cause nerve cell damage."
Prior
to the experiment, Holtzman and some other scientists
had regarded plaque damage to nerve cells as a fait
accompli — something that the plaques only needed to
inflict on nerve cells once. According to Holtzman,
the new results suggest that plaques might not just
cause damage but also somehow actively maintain it.
The
study, will appear in the Feb. 5 issue of the Journal
of Clinical Investigation.
Lead
author Robert Brendza, Ph.D., research instructor, began
the experiment with one key question: how did clearance
of brain plaques, made possible by the development of
Abeta antibodies, affect the progression of Alzheimer's
disease? Through collaborations with researchers at
other institutions, he had acquired several key techniques
and technologies that allowed him to closely track changes
in live brain cells in mice with an Alzheimer's-like
condition.
The
mice he used for the study had two mutations. One, utilized
by scientists at Eli Lilly, causes amyloid plaques to
build up, creating the Alzheimer's-like condition. The
second, developed by scientists at Washington University,
causes some of the mouse brain cells to produce a dye
that allowed Brendza to obtain detailed images of nerve
cell branches.
To
correlate brain cell changes with plaque development,
Brendza injected another dye, developed by scientists
at the University of Pittsburgh, that temporarily sticks
to amyloid. He showed that as the plaques appeared,
nearby branches of nerve cells developed bumps and swellings.
"If
you look under the electron microscope at these swellings,
they are filled with abnormal amounts of different types
of cellular parts known as organelles," Holtzman
explains. "Normally any given segment of a nerve
cell branch would have only very small amounts of these
organelles."
Nerve
cells move organelles along their branches as a part
of their regular function. Holtzman suspects that this
transport breaks down in the mice, leading to pileups
that become swellings. Scientists have previously demonstrated
that such swellings make it difficult or impossible
for nerve-cell branches to send signals.
After
showing that the swellings were mostly stable in number
and size over the course of three to seven days, Brendza
injected Abeta antibodies directly onto the surface
of the mouse brains. In the region of the injection,
the antibodies cleared the plaques, confirming earlier
research results. Then Brendza closely monitored the
swellings for three days.
"We
thought that clearing the plaques would halt the progression
of the damage—stop the development of new swellings,"
says Brendza. "But what we saw was much more striking:
in just three days, there were 20 to 25 percent reductions
in the number or size of the existing swellings."
The
nerve cells' rapid ability to regain normal structure
has Holtzman and Brendza wondering if the nerve cells
are constantly trying to restore their normal structure.
If so, that recuperative effort must somehow be countered
on an ongoing basis by the effects of the plaques.
More
research is needed to determine if similar effects will
occur in humans. Abeta antibodies are currently being
considered for use in Alzheimer's patients in clinical
trials.
In
the mice, the largest swellings were least likely to
heal. Brendza plans to look into whether additional
treatment can prompt their recovery.
Holtzman
and Brendza plan to continue using the mouse model to
study disease treatments and the cellular abnormalities
caused by their Alzheimer's-like condition.
"For
example, we'd like to know what's going wrong in the
nerve cell branches that get these swellings,"
Holtzman says. "Is it really a cellular transport
problem, or do the swellings result from the plaques'
effects on nearby support cells? Or is it something
else?"
Brendza
RP, Bacskai BJ, Cirrito JR, Simmons KA, Skoch JM, Klunk
WE, Mathis CA, Bales KR, Paul SM, Hyman BT, Holtzman
DM. Anti-Aß antibody treatment promotes the rapid recovery
of amyloid-associated neuritic dystrophy in PDAPP transgenic
mice. Journal of Clinical Investigation, January 20,
2005.
Funding
from the National Institutes of Health, Eli Lilly and
Company, Missouri Alzheimer's Disease and Related Disorders
Program, American Health Assistance Foundation, the
Hope Center for Neurological Disorders, and the Alafi
Family Foundation supported this research.
Washington
University School of Medicine's full-time and volunteer
faculty physicians also are the medical staff of Barnes-Jewish
and St. Louis Children's hospitals. The School of Medicine
is one of the leading medical research, teaching and
patient care institutions in the nation, currently ranked
second in the nation by U.S. News & World Report.
Through its affiliations with Barnes-Jewish and St.
Louis Children's hospitals, the School of Medicine is
linked to BJC HealthCare.
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