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THREADS OF
ALZHEIMER’S: The abnormal thread-like fibers (gray) that
characterize the brains of people with Alzheimer’s disease, as
revealed through nuclear magnetic resonance spectroscopy. The
colored molecules highlight the zipper architecture identified
by Roland Riek, Ph.D. |
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Graphic Shows 3-D Structure of Alzheimer's Brain as
It Zips Up Peptides
March 8, 2006 – Last November, researchers
announced the creation of a unique three-dimensional structure of the
long thread-like fibers that fill the brains of Alzheimer's disease
patients. This dynamic graphic was published in the February 2006 issue
of Inside Salk.
The structure reveals the proteins that make up the
fibrils lock onto each other much like a zipper on a jacket. This
advance, reported in the Nov. 14th early online edition of Proceedings
of the National Academy of Sciences (PNAS), helps illuminate the
molecular roots of Alzheimer’s and possibly other degenerative diseases
of the brain.
“Now that we understand at an atomic level how
these fibrils form, it might help researchers develop a biomarker test
to diagnose Alzheimer’s disease at an early stage, as well as drugs to
treat it,” says the study’s lead investigator, Salk Institute for
Biological Studies scientist Roland Riek, Ph.D., who collaborated with
researchers at the University of Lausanne and Roche pharmaceuticals,
both in Switzerland
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As a result of the study, Riek and his colleagues
may now understand how a potential Alzheimer’s disease medication now in
clinical trials in Europe reacts to the fibril. The drug binds to the
end of the fibril chain of beta amyloid proteins, halting their lethal
accumulation, an early step in the formation of the amyloid plaque
deposits that are a hallmark of Alzheimer’s.
Solving the structure of these fibrils may also
offer insights into other neurodegenerative diseases such as Parkinson’s
disease and Creutzfeldt-Jacok disease that develop fibrils due to errant
changes in the structural shape of brain proteins, adds Riek, assistant
professor in Salk’s Structural Biology laboratory.
“There are more than a dozen of these diseases, and
what we learn from one offers us insights into others,” he says. For
example, Riek and his colleagues described in the June 8 issue of Nature
how such a conformational change turns tiny protein particles into the
infectious molecules known as prions that are responsible for “mad cow
disease,” and they also showed how that process could be reversed.
The research team of the Salk Institute, in
collaboration with the University of Lausanne and Roche, developed new
research techniques to determine the 3D structure that mimics the most
common type of fibrils found in patients with the disease.
They discovered that beta amyloid proteins
(peptides) that make up these fibrils attach to each other on one end
with an ever-growing property
“From this structure we can nicely see what happens
physically, where the fibril forms a template on which to bind other
amyloid peptides in an inter-collated way,” Riek says. “The way these
peptides lock on to each other is like a zipper on a jacket.” Due to the
ever-growing property the zipper binds more and more loose peptides
together to produce dense “plaque” filaments that may be toxic to the
functioning of brain nerve cells.
In Alzheimer’s disease, amyloid plaque form when
enzymes cleave the amyloid precursor protein (APP), thereby releasing
the toxic beta amyloid fragments. Healthy brains can clear away excess
beta amyloid peptides, but for reasons that are not understood, these
proteins, made up of between 39-42 amino acids, change shape in some
people, leading to a sticky aggregation.
Riek already demonstrated how the flexible peptide
can be altered, and in this study, he showed how a clump of them can
attract and bind other molecules. “There are at least four stages needed
to get to the point where a structure is created that can form
filaments, and what we show here is that end stage.
Scientists are debating whether these long
filaments produce the nerve damage that results in dementia, or whether
the shorter, more mobile threads, which are also composed of beta
amyloid. Riek and his team are now working on solving the 3D structure
of these smaller aggregates, in their quest to sculpture the molecular
roots of Alzheimer’s disease.
Collaborating with Riek in the study, funded by Pew
Charitable Trusts, were Thorsten Luhrs, Ph.D., postdoctoral researcher
in the Structural Biology Laboratory, and Dave Schubert, Ph.D.,
Professor and head of Salk’s Cellular Neurobiology Lab. The Salk
Institute is in La Jolla, California.
Links:
>
Inside Salk - February 2006
>
Salk Institute
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