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Small molecule may play big role in Alzheimer's disease

Image of aggregation mechanism of Aβ42 protein, which plays a major role in Alzheimer's disease, in the absence or presence of the inhibitor Aβ(39-42).
Amyloid β-protein (Aβ) plays a significant role in Alzheimer's disease. Certain C-terminal fragments (CTFs) have been shown to be effective inhibitors of Aβ42, a form of the amyloid protein. Here we see the aggregation mechanism of Aβ42 in the absence or presence of the inhibitor Aβ(39-42). Normally Aβ42 forms soluble, neurotoxic oligomers before forming larger, fibrillar structures. Aβ(39-42) binds directly to Aβ42 monomer and oligomeric species and eliminates the formation of large Aβ42 oligomers, driving the formation of nontoxic oligomeric species which also eventually form fibrils. Above image courtesy TACC.
Front page image of PET scan of human brain with Alzheimer's disease courtesy Wikimedia Commons.

Alzheimer's disease is one of the most dreaded illnesses facing older Americans, but there is no consensus on the underlying mechanism of the disease.

A team of researchers is using powerful computer simulations to explore the hypothesis that toxicity in the brain is caused by small and transient molecules, and has found new ways to inhibit their formation.

"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."

Since 2007, Shea has run thousands of simulations of amyloid peptides using the Rangersupercomputer at the Texas Advanced Computing Center (TACC) to better understand the structure, formation, and behavior of amyloid accumulations.

"We can identify the important structures that are adopted by [amyloid] peptides at a resolution that exceeds what can be done experimentally," she said. "This helps us understand what structures lead to a self-assembly."

Accumulations of amyloid plaques have long been associated with the disease and were presumed to be its cause. These long knotty fibrils form from 'misfolded' protein fragments, and 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. 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, Michael Bowers, professor of chemistry and biochemistry at UCSB, and a third 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 damage to the membrane," Shea 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.

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 stopped the formation of oligomers, possibly halting disease progression before it is too late.

"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 TACC's Ranger and Lonestar high-performance computers helped researchers identify where the inhibitors bind and led to new ideas about how inhibition can be improved.

The projects have required more than 13 million hours of compute time since 2009.

"The number of atoms is huge-we need a lot of computational resources to simulate them. Nothing that we're doing here is something that we could do on our home clusters. The scale of it is intractable," Shea said.

Ranger and Lonestar are part of the Extreme Science and Engineering Discovery Environment (XSEDE), the NSF-funded effort to provide e-infrastructure and computing power to US scientists.

"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."

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