Article Date: 08 Apr 2008 - 7:00 PDT
Leaky blood vessels that lose their ability to protect the spinal cord from
toxins may play a role in the development of amyotrophic lateral sclerosis,
better known as ALS or Lou Gehrig's disease, according to research published in
the April issue of Nature Neuroscience.
The results mark the
first time that scientists have witnessed molecular changes occurring long
before key nerve cells start dying. The unexpected finding opens up a new front
in studies of ALS, a disease in which motor neurons in the spinal cord die off
for unknown reasons, resulting in dramatically weakened muscles. Patients lose
their strength, their ability to move or swallow, and eventually lose their
ability even to breathe. Most patients live only a few years after diagnosis.
"We believe these changes contribute to or possibly initiate the onset
of ALS," said lead author Berislav Zlokovic, M.D., Ph.D., of the University of
Rochester Medical Center. "It's clear that these changes occur before the loss
of neurons, and it's well known that the types of changes we are seeing
certainly injure or kill these types of cells, which are extremely sensitive to
their biochemical environment."
The results, discovered by studying
mutant mice that have an inherited form of the disease, were made by a
collaboration of neuroscientists from the University of Rochester Medical Center
working together with a team of ALS experts from the University of California at
San Diego. Zlokovic, a pioneer in learning how the body's vascular system plays
a role in neurodegenerative diseases like Alzheimer's disease and ALS, led the
team, and the first author is post-doctoral researcher Zhihui Zhong, Ph.D.
While it's unlikely the new findings will help ALS patients immediately,
the results open up a new and unexpected way to think about the disease.
Zlokovic's team is currently testing in the laboratory a compound that may help
seal up leaky vessels and protect the neurons targeted by ALS.
studied mice with a mutation in a gene for superoxide dismutase 1 (SOD-1), which
in healthy people and mice plays an important role keeping cells safe from
damaging molecules known as free radicals. Scientists estimate that SOD-1
mutations play a role in a small number of cases of ALS overall in people, about
one-quarter of the 10 percent or so of cases that are inherited. But those cases
provide a unique window to study the disease's initial steps.
paper, the group from Rochester's Center for
Neurodegenerative and Vascular Brain Disorders and UCSD showed that a breakdown
in the natural barrier between the blood and the spinal cord breaks down early
on in mice destined to get ALS, long before nerve cells appear sick or die.
In this work, the team showed that the barrier between the blood and the
spinal cord weakens in all three types of genetically based ALS cases that
involve SOD-1 mutations, allowing toxic substances to flood into the spinal cord
and directly affect neurons.
That barrier is crucial for the health of
our central nervous system, which is treated like the inner sanctum of the body.
Like a high-performance race car that demands a choice fuel, our neurons work
well only if the chemical environment in the brain and spinal cord is precisely
maintained within a strict, narrow set of conditions.
To maintain that
select environment, the body has strict barriers or gateways for substances
entering or exiting the central nervous system. Blood vessels run through our
brain and spinal cord and supply oxygen and other nutrients, and the lining of
those blood vessels constitutes a biochemical barrier to protect the central
nervous system from toxins, inflammatory cells, red blood cells, blood products,
and a variety of other potential toxic insults.
The barrier between the
blood and the spinal cord isn't some stand-alone structure that keeps all
substances away from the spinal cord. Rather, the word "barrier" describes an
elaborate molecular lattice that lines the insides of the blood vessels that
weave throughout the spinal cord. The lattice controls which molecules can cross
from the blood to the neurons in the spinal cord, and which cannot. It's a bit
like netting with very small openings that line the inside of blood vessels.
Oxygen and many nutrients get the OK to pass through the barrier in
measured amounts. And the barrier readily accepts waste products from the spinal
cord, transporting them away from the central nervous system and eventually out
of the body. But the "netting" should be taut and should bar substances in the
blood that have no business being near neurons.
The team found that a
SOD-1 mutation disrupted key building blocks in the barrier. Essentially, the
mutations loosened the lattice, creating bigger holes in the barrier that
allowed molecular interlopers to pass from the blood to the spinal cord.
Mice with the mutation had lower levels of three types of "tight
junction proteins" that are key components of the barrier: ZO-1, occludin and
claudin-5. In mice just two months old, the numbers of those important tight
junction proteins in the linings of blood vessels were reduced by about half, by
40 to 60 percent, allowing the lattice to loosen abnormally.
weakened barrier brought about several problems. Neurons were exposed directly
to biochemical byproducts of hemoglobin, which forms reactive oxygen molecules
that injure neurons. Where the barrier had weakened, tiny hemorrhages dotted the
spinal column. The smallest blood vessels crucial to nerve health shrunk: Mice
with the mutation had total capillary length in the spinal cord 10 to 15 percent
less than healthy mice, and their blood flow in the spinal cord was reduced by
30 to 45 percent.
Scientists must investigate whether the same processes
happen in forms of ALS that are not inherited. Zlokovic notes that from what is
known so far, the disease progresses exactly in inherited forms and forms that
are not inherited.
"The vascular system is crucial to health - it's how
oxygen and other nutrients are delivered to cells, and how toxins are removed,"
said Zlokovic, who is professor of Neurosurgery and Neurology and director of
the Center for Neurodegenerative and Vascular Brain Disorders. "Any damage to
the vascular system is a serious threat to the organism. It's clear now that the
vascular system is certainly involved in the development of ALS."
Zlokovic first began doing research on the disease in 2004, when a
former classmate from medical school who had been diagnosed with ALS and was
looking for new treatments contacted him. By the time his friend died two years
later, Zlokovic was well underway in studies investigating the possible role of
the vascular system.
During the last 15 years, Zlokovic has pioneered
the view that the vascular system plays a central role in many neurodegenerative
diseases. He has found that a breakdown in the barriers between the blood and
the central nervous system may be at the root of diseases like Alzheimer's. In
January, Zlokovic reviewed the evidence for involvement of the barrier in
diseases like Alzheimer's, ALS, and multiple sclerosis in a 24-page review in
----------------------------Article adapted by
Medical News Today from original press
The research team included
Zlokovic, Zhong, and Don Cleveland, Ph.D., a widely recognized ALS expert who is
a researcher at the University of California at San Diego. Previously, Cleveland
has shown that cells besides neurons in the spinal cord, such as astrocytes and
microglia, have an effect on the course of the disease.
Other authors of
the paper include Rashid Deane, Ph.D., associate professor; medical student
Zarina Ali; technical associate Margaret Parisi; Kerry O'Banion, M.D., Ph.D.,
associate professor of Neurobiology and Anatomy; graduate student Yuriy
Shapovalov; former student Konstantin Stojanovic; post-doctoral researcher Abhay
Sagare, Ph.D.; and post-doctoral fellow Séverine Boillée of UCSD. The National
Institutes of Health and the Muscular Dystrophy Association funded the work.
Source: Tom Rickey University of Rochester Medical Center