Alzheimer's, Dementia & Mental Health
Two Cardiovascular Proteins Pose a Double Whammy in
Alzheimer's Disease
Fuel AD by reducing blood flow to brain, slowing
rate of amyloid beta removal
Dec. 22, 2008 - Scientists were surprised at their
discovery that puts two proteins known for their role in the
cardiovascular system front and center in the development of Alzheimer's
disease. The two proteins which work in tandem in the brain's blood
vessels present a double whammy in AD. Not only do the proteins lessen
blood flow in the brain, but they also reduce the rate at which the
brain is able to remove amyloid beta, the protein that builds up in
toxic quantities in the brains of patients with the disease.
"This is quite unexpected," said Berislav Zlokovic,
M.D., Ph.D., a neuroscientist and a senior author of the study.
"On the other hand, both of these processes are
mediated by the smooth muscle cells along blood vessel walls, and we
know that those are seriously compromised in patients with Alzheimer's
disease, so perhaps we shouldn't be completely surprised."
The new findings are the result of a seven-year
collaboration between two laboratories. Zlokovic heads the Center for
Neurodegenerative and Vascular Brain Disorders, looking at molecular
roots of diseases like Alzheimer's.
Several years ago, after he found that several
genes well known to cardiovascular researchers seemed to be especially
affected in Alzheimer's patients, he turned to Joseph Miano, Ph.D. to
help analyze the findings. Miano is interim director of Aab
Cardiovascular Research Institute and associate professor of Medicine,
and he is senior co-author of the new study.
"To some, it might seem odd that a cardiovascular
group would intersect with a neuroscience group to study Alzheimer's
disease," Miano said.
"But there's a great deal of evidence to suggest
that Alzheimer's disease is a problem having much to do with the
vascular plumbing. And Rochester is the type of institution where
partnerships like these are easy to strike up."
For 15 years Zlokovic's laboratory has focused on
the molecular mechanisms regulating blood supply and the role of the
blood-brain barrier in the development of Alzheimer's disease. It's not
simply that reduced blood supply hurts brain cells by causing a shortage
of oxygen and other nutrients. Rather, deterioration of blood flow seems
to gum up the brain's ability to remove toxic amyloid beta.
Normally, amyloid is picked up efficiently by blood
vessels that then whisk the toxic trash away. But in Alzheimer's
disease, the system no longer is able to keep up with the body's
production of the substance. The molecular trash accumulates, and
Zlokovic and others believe the buildup kills brain cells.
The current work focuses on two proteins well known
to cardiovascular researchers, SRF (serum response factor) and
myocardin.
The two work together within smooth muscle cells
that line blood vessels to activate genes that are necessary for smooth
muscle to function properly. SRF binds to certain snippets of DNA called
CArG boxes and serves as an anchor, while myocardin piggybacks along and
turns on the genes to which SRF sticks.
Together they act as a master switch that
determines whether smooth muscle cells contract one of many ways the
body controls just how much blood is flowing in the body.
Two years ago, Zlokovic and Miano published a study
showing that the two proteins are much more active in the blood vessels
of brains of people with Alzheimer's disease than in people who do not
have the disease. They showed that when they reduced the activity of the
proteins, blood flow in the brain increased, and when the genes were
more active, blood flow decreased.
The latest report goes further, implicating the
molecular duo in the slowed removal of amyloid beta. The team found that
SRF and myocardin working together turn on a molecule known as SREBP2.
That protein inhibits a molecule known as LRP-1, which helps the body
remove amyloid beta. In other words, when SRF and myocardin are active,
toxic amyloid beta accumulates.
The findings came primarily from the team's studies
of brain cells taken from people who had Alzheimer's disease and
comparing them to cells from healthy elderly people.
Compared to the smooth muscle cells from healthy
adults, the cells from patients with Alzheimer's disease had about five
times as much myocardin and four times as much SRF, about five times as
much SREBP2, and about 60 percent less LRP-1. That translated into a
reduced ability to remove amyloid beta: Cells taken from patients with
the disease had only about 30 percent of the ability to remove the
substance as cells taken from their healthy counterparts.
When the team lowered levels of SRF to the same
level that exists in healthy cells, the cells from Alzheimer's patients
improved in their ability to remove amyloid beta, doing it just as well
as cells from healthy individuals. Conversely, when the team boosted
levels of SRF and myocardin in the healthy cells, the changes lowered by
about 65 percent those cells' ability to remove amyloid beta.
In mice, the team found parallel results. When the
team boosted SRF or myocardin in healthy mice, those mice had about
twice as much SREBP2 in their smooth muscle cells in the brain's blood
vessels. They also had 90 percent less LRP-1, three times as much
amyloid beta in their arteries, and 70 percent more amyloid beta in
their brain tissue.
When the team reduced SRF and myocardin in mice
prone to developing Alzheimer's disease, those mice had 60 percent less
SREBP2, about four times as much LRP-1, and a 50-percent reduction in
amyloid beta in their blood vessels.
The first author of the study is Robert Bell, a
graduate student in Zlokovic's laboratory who is in Department of
Pathology and Laboratory Medicine's graduate program. He had searched
for months, without success, for evidence of a direct effect on LRP-1 by
SRF/myocardin. A subsequent literature search turned up findings that
the molecules might affect SREBP2. With that finding, the team was able
to move forward and put the whole picture together.
Now the team has turned its attention to studying
the role of hypoxia, which seems to play a role in turning on myocardin,
as well as searching for molecules that block the hookup between SRF and
myocardin.
The work, described in a paper published online
Dec. 21 in the journal Nature Cell Biology, provides hard evidence
directly linking two processes thought to be at play in Alzheimer's
disease: reduction in blood flow and the buildup of toxic amyloid beta.
The research should make the interaction between the two proteins a
seductive target for researchers seeking to address both issues.
Background Information
The work was funded primarily by the National
Institute on Aging. Other funding came from the National Institute of
Neurological Disorders and Stroke, and from Socratech Laboratories, a
company founded by Zlokovic that is seeking to commercialize discoveries
related to his work on Alzheimer's disease and stroke. Both Zlokovic and
Miano hold a significant equity stake in the company.
In addition to Bell, Miano and Zlokovic, other
authors of the paper include Rashid Deane, Ph.D., research professor;
Nienwen Chow, Ph.D., a scientist at Socratech; Xiaochun Long, Ph.D.,
research assistant professor; Abhay Sagare, Ph.D., instructor;
post-doctoral associate Itender Singh, Ph.D.; Jeffrey Streb, Ph.D., a
former graduate student and now a post-doctoral researcher at UCLA;
Huang Guo, Ph.D., research assistant professor; pathologist Ana Rubio,
M.D., Ph.D.; and William Van Nostrand, Ph.D., of Stony Brook University
Medical Center.
