Berislav V. Zlokovic talks
with ScienceWatch.com and answers a few questions
about this month's Emerging Research Front Paper in the
field of Neuroscience & Behavior.
Article: RAGE mediates amyloid-beta peptide
transport across the blood-brain barrier and accumulation
Authors: Deane, R, et al.
Journal: NATURE MED, 9 (7): 907-913 JUL 2003
Addresses: Univ Rochester, Med Ctr, Dept Neurosurg, Frank P
Smith Labs Neurosurg, Rochester, NY 14642 USA.
Univ Rochester, Med Ctr, Dept Neurosurg, Frank P Smith Labs
Neurosurg, Rochester, NY 14642 USA.
Univ Rochester, Med Ctr, Ctr Aging & Dev Biol, Div
Neurovasc Biol, Rochester, NY 14642 USA.
(addresses have been truncated.)
Why do you think your paper is highly
Since the publication of our article in 2003, there has been an increased
interest in RAGE (receptor for advanced glycation endproducts) as a
transporter of Aß into brain, and on the effects of Aß/RAGE
Our paper showed that RAGE is increased in the blood vessels of a mouse
model of Alzheimer's disease (AD), and that this increased level of RAGE is
associated with greater entry of the AD toxin Aß into brain. This
supports the vascular hypothesis of AD, i.e., that blood vessels contribute
to the causes of AD.
This paper also showed that Aß/RAGE interaction caused the following:
1) an increased release of a chemical, endothelin-1, that causes the brain
blood vessels to constrict and may contribute to reduce brain blood flow as
seen in AD, 2) raised levels of oxidative stress markers, and 3) raised
levels of inflammatory chemicals. Blocking the Aß/RAGE interaction
prevented these responses. These studies showed that RAGE is a potential
target for the development of new therapies for AD.
"The blood vessels of the brain are
unique and form the physical site of the BBB,
which restricts the passage of molecules into
and out of the brain."
These studies may have stimulated research on the role of RAGE in various
diseases, including AD and diabetes, and on the development of new
therapies. This may have explained the high citation rate.
Does it describe a new discovery, methodology, or
synthesis of knowledge?
Since scientific studies of this nature are published based on novelty,
it's probably a new discovery.
Would you summarize the significance of your paper in
This paper shows the importance of the brain blood vessels in transporting
the toxin Aß into brain. It also identified the main transporter,
RAGE, that ferries the AD toxins into brain. It also showed that
Aß/RAGE interaction caused reduced brain blood flow, inflammation,
and oxidative damage, which are also associated with AD. Blocking this
interaction reversed these effects. RAGE is a potential target for the
development of new AD therapies.
How did you become involved in this research and were any particular
problems encountered along the way?
I was trained at the King's College London, by the renowned British
physiologist, Dr. Hugh Davson—1909-1996—who was known as the
father of the blood-brain barrier (BBB). A recent review on the BBB was
dedicated to him (Zlokovic B, Neuron. 57: 178-201, 2008).
The blood vessels of the brain are unique and form the physical site of the
BBB, which restricts the passage of molecules into and out of the brain. I
became involved in AD research when a colleague, Dr. Blas Frangione, a
Professor of Pathology and Psychiatry at the NYU School of Medicine,
suggested that I applied my BBB research to AD.
We first published a study on Aß transport into the brain in 1993
(Zlokovic B, et al., BBRC 197: 1034-40, 1993). We then
investigated mechanism of Aß transport into and out of the brain. Our
studies showed that the main transporter that transports Aß out of
the brain is LRP1 (low-density lipoprotein related protein 1), and the main
transporter that transports Aß into brain is RAGE.
Where do you see your research leading in the
My work is focused on translational research, working towards developing
new therapies for AD and stroke. Regarding RAGE, we have identified a small
compound that blocks the interaction of Aß with RAGE. In a mouse
model of AD, this compound reduced brain Aß levels and improved
functional changes in brain blood flow and behavioral performance. This
compound is a potential new therapy for AD.
Do you foresee any social or political implications for
If this compound, or its chemical entity, became a treatment for AD and
other RAGE-dependent diseases, then it may indeed have social benefits.
Berislav V. Zlokovic, M.D., Ph.D.
Professor of Neurosurgery and Neurology
Director, Center for Neurodegenerative & Vascular Brain Disorders
University of Rochester Medical Center
Rochester, New York, USA
Keywords: receptor for advanced glycation endproducts,
aß/rage interaction, low-density lipoprotein related protein 1,
reduced brain blood flow, inflammation, oxidative damage, alzheimer's
disease, diabetes, endothelin-1, oxidative stress markers, inflammatory
chemicals, hugh davson, blood-brain barrier.