Metal Ions Linked to Neurodegenerative Disease
06 August 2007
Researchers Link Metal Ions to Neurodegenerative Disease
multi-institutional team of researchers led by Emory University has
defined for the first time how metal ions bind to amyloid fibrils in
the brain in a way that appears toxic to neurons. Amyloid fibrils are
linked to the development of neurodegenerative diseases such as
Alzheimer's, Parkinson's and Creutzfeldt-Jakob. Although metal ions,
most notably copper, can bind to amyloid in several specific ways, the
researchers found that only one way appears toxic.
will appear in the Proceedings of the National Academy of Sciences,
Early Edition online during the week of Aug. 6-10 and in the Aug. 14
Copper ions, atoms that have acquired an electric
charge by gaining or losing one or more electrons, are found naturally
in the brain, as are other ions such as zinc and iron. Increasing
evidence now links these naturally occurring ions to amyloid assembly
and to Alzheimer's disease, says David Lynn, PhD, Emory professor and
chair of chemistry and principal investigator of the study.
little is known about the exact mechanisms governing the formation of
amyloid fibrils, the study's results suggest that the exact way amyloid
binds to copper ions affects the fibers' architecture, rate of
propagation and their effect, if any, on surrounding neurons.
all amyloid fibrils are toxic," says Dr. Lynn. "Amyloid is made of
proteins and proteins normally fold into beautiful structures. However,
for whatever reason, some misfold and the resulting misfolded
structures are also beautiful, but sticky. They stick to themselves and
then propagate to form fibrils, but only some of the fibrils turn out
to be toxic."
Those who suffer from Alzheimer's disease, for
example, have an unusual amount of sticky amyloid fibrils in their
brains. Over time, the fibrils accumulate instead of decomposing and
increasingly interfere with the brain's structure and function. In
contrast, normally folded proteins are cleared from the brain shortly
after they are produced.
The scientists, collaborating
throughout the United States and across Emory, focused on the smallest
individual unit of amino acids that make up amyloid fibrils. By
determining only an individual unit's physical and chemical properties
when binding with metal, the researchers were able to determine the
activity governing the assembly and toxicity of whole fibrils with
respect to their effect on brain cells.
"We showed that the
activity of this minimal unit actually replicates the activity of the
whole fibril on the neuronal cell. And it does so by binding the metal
in a specific way," says Dr. Lynn.
Forty years ago, scientists
began exploring a possible link between overexposure to metals and
Alzheimer's disease. Because some people with the disease had aluminum
deposits in their brains, it was thought that there was a direct
connection between aluminum exposure and Alzheimer's. However, after
many years of study, no conclusive evidence links aluminum to
neurodegenerative disease, which leaves researchers to focus on zinc,
iron and copper.
The researchers also found that several
distinct types of structures could be assembled from individual units
of amino acids. "We found that we could build lots of different types
of structures with an individual unit: fettuccine-shaped structures,
tubes, vesicles, and so on, not just fibers. And this is remarkable,"
says Dr. Lynn.
"Our findings now lead us to ask what other types
of structures these individual units can make, what exactly happens
when the units bind to one another, and whether these individual units
are important to neurodegenerative diseases or whether the entire
fibril must be involved," says Dr. Lynn.
"Like many scientific
findings, we know about amyloid because of the diseases it's associated
with rather than because of its benefits," says Dr. Lynn. "However,
researchers are also finding situations in which amyloid is beneficial,
such as in long-term memory and synapse maintenance in the marine
The study, which was conducted in collaboration with the
University of Georgia and the Stanford Linear Accelerator Center
(SLAC), was supported by the Department of Energy and the National
Institutes of Health through a core grant to the Alzheimer's Disease
Research Center and to SLAC. The team of researchers from Emory
included Dr. Lynn, Jijun Dong, Anil Mehta, Seth Childers, and James
Simons, Departments of Chemistry and Biology; Jeffrey Canfield and Kurt
Warncke, Department of Physics; Bo Tian, and Zixu Mao, Department of
Pharmacology; and Robert Scott, Department of Chemistry, University of
Georgia and SLAC.
Emory University's Woodruff
Health Sciences Center is one of the nation's pre-eminent academic
health centers, devoted to Making People Healthy through research,
teaching, and patient care. It includes the Emory University School of
Medicine, the Rollins School of Public Health, the Nell Hodgson
Woodruff School of Nursing, and the Yerkes National Primate Research
Center. Its clinical arm is Emory Healthcare, Georgia's largest and
most comprehensive health care system, consisting of Emory University
Hospital, Emory Crawford Long Hospital, Wesley Woods Center, The Emory
Clinic, the Emory Children's Center, EHCA, LLC, Emory-Adventist
Hospital, and other affiliates.
© Emory University 2007