Alzheimer's disease is one of the most dreaded and debilitating
illnesses one can develop. Currently, the disease afflicts 6.5 million
Americans and the Alzheimer's Association projects it to increase to between 11
and 16 million, or 1 in 85 people, by 2050.
Cell death in the brain causes
one to grow forgetful, confused and, eventually, catatonic. Recently approved
drugs provide mild relief for symptoms but there is no consensus on the
underlying mechanism of the disease.
"We don't know what the
problem is in terms of toxicity," said Joan-Emma Shea, professor of
chemistry and biochemistry at the University of California, Santa Barbara
(UCSB). "This makes the disease difficult to cure."
Accumulations of amyloid plaques
have long been associated with the disease and were presumed to be its cause.
These long knotty fibrils, formed from misfolded protein fragments, are almost
always found in the brains of diseased patients. Because of their ubiquity,
amyloid fibrils were considered a potential source of the toxicity that causes
cell death in the brain. However, the quantity of fibrils does not correspond
with the degree of dementia and other symptoms.
New findings support a hypothesis
that fibrils are a by-product of the disease rather than the toxic agent
itself. This paradigm shift changes the focus of inquiry to smaller,
intermediate molecules that form and dissipate quickly. These molecules are
difficult to perceive in brain tissue.
Shea's group uses computer
simulations to understand the formation of toxic entities in the brain. Since
2007, Shea has run thousands of simulations of amyloid peptides using the
Ranger supercomputer at the Texas Advanced Computing Center (TACC) to better
understand the structure, formation and behavior of amyloid accumulations.
"We can identify the
important structures or conformations that are adopted by these peptides at a
resolution that exceeds what can be done experimentally," she explained.
"This helps us understand what structures lead to a self-assembly."
For decades, it was believed that
fibrils were a toxic species, but increasingly researchers are looking at
small, soluble precursor forms of the fibrils, known as oligomers. "These
are difficult to detect experimentally because they tend to be transient
species," Shea said "There's no consensus on how big they are. There
are still a lot of debates."
Shea and Michael Bowers,
professor of chemistry and biochemistry at UCSB and Shea's experimental
collaborator, believe the transient oligomers may be responsible for the onset
of the disease through interactions with the cell membrane.
"These oligomers may be
toxic by inserting themselves into membranes and causing a damage to the
membrane," she said. "The membrane is critical for the cell
viability."
In 2007, Shea and Bowers received
a grant from the National Institutes of Health to investigate this theory.
Together, they have spent the last five years looking at small peptide-based
inhibitors that would prevent these oligomers from forming.
"If you can prevent the
oligomers from forming, you can limit toxicity," Shea said.
In a recent paper currently in
press in Biophysical Journal, Shea and postdoctoral researcher Luca Larini
studied the conformations adopted by small oligomers of peptide amyloids
encountered within the cell. They found that hairpin-shaped forms of the
peptide initiated the aggregation of oligomers that ultimately led to the
formation of a fibril. Like an old slapstick routine where one person trips,
another trips over them, and eventually a pile forms, the misfolded proteins in
the brain cells of those with Alzheimer's recruit other misfolded proteins and
eventually grow into a large mass.
Shea's simulations have not only
helped uncover the possible role of oligomers in the onset of Alzheimer's, but
they are aiding in research that is trying to stop oligomer formation in the
first place. A paper in the November 2011 edition of Biochemistry, co-authored
with the Bowers group, described how a class of small molecules known as
c-terminal inhibitors was able to stop the formation of oligomers, possibly
halting disease progression before it is too late.
"Dr. Shea's simulations put
a molecular face on the cross sections and oligomer distributions that we
experimentally measure," said Bowers. " Of significant importance is
the simulation of the ABeta42 monomer structure that very nicely correlated
with our experiments. Also of importance are calculations on the sites and
mechanism of attachment of potential therapeutic agents that we are testing as
ABeta aggregation inhibitors."
Simulations on Ranger helped
researchers identify where the inhibitors bind and led to new ideas about how
inhibition can be improved.
"Dr. Shea is clearly at the
top of the large cohort of simulators in her age group," Bowers said.
Through a related investigation,
Shea and postdoctoral researcher Chun Wu solved the long-standing mystery of
why Thioflavin T, a dye commonly used in brain imaging, is able to bind to
amyloid proteins. Her molecular dynamics simulations identified the specific
hydrophobic motif in the peptide to which the dye binds. This pinpoint
conclusion now allows chemists and neurological experimentalists to create
designer forms of the dye that can be used to improve their diagnostic ability.
These results were reported in the Biophysical Journal in March 2011.
"Now that we've established
where these molecules bind, we can start tweaking the molecule to try to make
binders that have a greater affinity for the fibril. That could be something
that would be beneficial for medicine as a better imaging agent," she
said.
Shea's simulations of peptide
interactions, dyes binding to fibrils, and inhibitors stopping the accumulation
of amyloids provide great insights to scientists. The projects required more
than 13 million hours of compute time on TACC's Ranger and Lonestar
supercomputers since 2009.
"The number of atoms is
huge—we need a lot of computational resources to simulate them," Shea
said. "Nothing that we're doing here is something that we could do on our
home clusters. The scale of it is intractable."
Ranger is one of the top 50 most
powerful supercomputers in the world, Funded by the National Science Foundation
and deployed in 2008, Ranger helps scientists around the country make
discoveries by offering free compute time to academic researchers. The system
is part of the Extreme Science and Engineering Discovery Environment (XSEDE),
the NSF-funded effort to provide cyberinfrastructure and computing power to the
nation's scientists.
In February, Ranger will be
decommissioned to make way for Stampede, a new supercomputer 20 times more
powerful. Such a system will be required to answer further important questions
about Alzheimer's disease.
"With growing computational
resources and capabilities, we'll be able to look at how these proteins
interact with membranes," Shea said. "We're far away from simulating
a whole cell, but we can start incorporating additional elements that may turn
out to be important."
Source: Texas Advanced
Computing Center
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