Source: University Of Kentucky Medical Center (http://www.mc.uky.edu/)
Date: Posted 6/5/2000
New Potential Drug Target For Alzheimer's Disease
Researchers at the University of Kentucky College of Medicine and the
Columbia University College of Physicians and Surgeons have determined that a
cell receptor, called RAGE, may be a new potential target for compounds that
may treat or prevent Alzheimer's disease.
The study leaders were Shi Du Yan, M.D., assistant professor of pathology,
and David Stern, M.D., professor of physiology and cellular biophysics and of
surgery, both at the Columbia University College of Physicians and Surgeons,
and Mark Kindy, Ph.D., associate professor of biochemistry at the UK College
of Medicine, UK Sanders-Brown Center on Aging, Stroke Program at the UK
Chandler Medical Center, and Veterans Affairs Medical Center in Lexington.
The results of the research are published in the June issue of Nature
About 60,000 Kentuckians have Alzheimer's disease, and, nationally, 4 million
people are estimated to have the disease. A protein called amyloid-beta is
thought to be critical in the development of Alzheimer's disease, although
the exact role of amyloid-beta is unknown. Aggregated amyloid-beta proteins,
also called amyloid fibrils, are found in the brains of Alzheimer's patients
and cause tissue damage and eventually death.
The UK researchers have shown that a receptor -- called the receptor for
advanced glycation endproducts (or RAGE) and located on the surface of
certain neurons -- interacts with amyloid fibrils. RAGE is a multiligand
receptor, meaning that it interacts with many molecules. When RAGE interacts
with the amyloid fibrils, it accelerates fibril formation and induces
UK researchers disrupted the interaction of RAGE with amyloid fibrils two
ways. They added additional amounts of soluble RAGE to neurons with amyloid
fibrils. Because the RAGE molecules were not linked to cells, they could
interact with the fibrils but not cause cellular dysfunction. They also added
an antibody to RAGE that would bind to the receptor and prevent any
interaction with amyloid fibrils.
Both methods suppressed amyloid formation in a systemic model of amyloid
diseases, including Alzheimer's disease. In addition, by blocking RAGE with
an antibody, the researchers found that the process of amyloid fibril
deposition was reversed.
"The exciting thing about this research is that it suggests that RAGE may be
a potential target for inhibiting amyloid fibril deposition, which would
likely inhibit the progression of Alzheimer's disease," Kindy said.
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