[alscenter] PACKARD CENTER UPDATE: Leaky Blood Vessels and ALS


From: alscenter@jhmi.edu

To: The ALS Community

Date: June 16, 2008

Subject: Robert Packard Center ALS News Network

View this article online at:
http://www.alscenter.org/news/briefs/080610.cfm

LEAKY BLOOD VESSELS ADD TO ALS DAMAGE, COULD OFFER NEW REPAIR SITE

This spring, scientists reported on an unsuspected source of early
damage in ALS - it involves blood vessels - that apparently strikes
before disease symptoms begin. Its earliness and relative easy access -
should a therapy come, at some point - are sure to spark more research,
the investigators say.

Packard scientist Don Cleveland and colleagues described new studies in
ALS animal models, showing harm to certain blood vessels important to
spinal cord health. The work also singles out specific blood vessel
proteins that are damaged.

A report of their work appeared in the April issue of Nature
Neuroscience.

Specifically, Cleveland and the team noted injury to the blood-spinal
cord barrier (BSCB) that separates the spinal cord from the rest of the
body. It's a divider made in part of closely touching blood vessels
and protects the spinal cord from toxins and undesirable immune cells.

The work joins studies Cleveland's lab has carried out over the past
six years that methodically look at all cells and other nervous system
structures, trying to find what part, if any, each plays in ALS.
Earlier research, for example, shows two types of cells, astrocytes and
microglia, help the disease to progress.

In this project, the team studied the BSCBs and spinal cords of two
different types of ALS model mice, each carrying a version of the mutant
human gene - called SOD1 - that causes a common inherited form of the
disease in people. They compared the mice with healthy controls whose
SOD1 genes were normal.

In the ALS model mice, at an early age, the BSCB was damaged enough to
let antibodies enter the spinal cord. The more the disease progressed,
the more antibodies got through.
Also, the presence of hemosiderin, a blood breakdown product, both
inside and around the spinal cord's motor neurons, alerted the
scientists to hundreds of small leaks in the BSCB's blood vessels.

The early breakdown of the BSCB, the researchers say, occurs before the
inflammation that typically hits motor neurons in animal models and in
patients later in ALS. This suggests that it's the presence of the
mutant SOD1 protein in blood vessel cells, rather than inflammation,
that might be damaging the protective barrier.

They showed this is the case by examining the capillaries that are
"baby" forms of the BSCB. In model mice with the mutant SOD1 gene,
three key proteins that act like molecular staples to hold blood vessel
cells tightly together were in short supply.

"This tells us that mutant SOD1 somehow disrupts the BSCB by making
the proteins that hold it together less available," Cleveland
explains.

The total length of the capillaries in the lumbar spinal cord was also
reduced. And the scientists found fluid had collected between the vessel
walls and nearby motor neurons. While all this would certainly seem to
be harmful, the team went a step farther to show that.

Direct measurement with a radioactive isotope showed that blood flow
was cut as much as 45 percent through the cervical and lumbar spinal
cord by the time the model mice were two months old. Flow was most
reduced in areas affecting motor neurons.

Exactly what could injure motor neurons is unclear, though reduced
oxygen and the presence of toxic molecule from the breakdown of blood
cells are certain suspects.

"Our study shows that damage to blood vessels is one of the earliest
sources of harm in the toxic cascade that mutant SOD1 unleashes," says
Cleveland. "The breaks - hemorrhages - in the BSCB's blood vessels
let toxic products in while they cut normal blood flow. This is one more
instance, in inherited ALS, where motor neurons are harmed from without.
We're looking into possible drug or gene-therapy approaches, however,
that might keep the BSCB intact. That, possibly, could delay disease
onset or its progress."

Cleveland is at the University of California, San Diego, as is his
co-researcher, Severine Boillee. Their colleagues, including senior
author Berislav Zlokovic, are from the University of Rochester.

___________________________________

About The Robert Packard Center for ALS Research at Johns Hopkins
http://www.alscenter.org/

Located in Baltimore, the Robert Packard Center for ALS Research at
Johns Hopkins is a worldwide collaboration of scientists aimed at
developing therapies and a cure for amyotrophic lateral sclerosis (ALS),
also known as Lou Gehrig's disease.

The Center is the only institution of its kind dedicated solely to the
disease. Its research is meant to translate rapidly from the lab bench
to the clinic, largely by eliminating time spent waiting for grants and
lowering institutional barriers to sharing scientific results.

Scientists and clinician members of the Packard Center have moved drugs
reliably and rapidly from preclinical experiments to human trials.
Direct or indirect links to international biotech or pharmaceutical
companies bring the infrastructure and experience needed to make
promising drugs into therapies.

Packard scientists are the first to propose and test a combination
approach to drug therapy, a tactic that has worked for AIDS, cancer and
other diseases.

ALS is a progressive, disabling neuromuscular disease that causes
complete paralysis and loss of function - including the ability to
eat, speak and breathe. ALS progresses quickly and is not curable. Most
patients die within five years of diagnosis.


_________________________________________
Rebecca Berger
Research Program Coordinator
Robert Packard Center for ALS Research at Johns Hopkins
5801 Smith Avenue | McAuley Suite 110
Baltimore, MD 21209
410.735.7678 direct
410.735.7680 fax
rberger6@jhmi.edu
http://www.alscenter.org/