June 2, 2008

Molecule Dissolves Fibers Found in Alzheimer’s Disease Patients

Panel on left shows network of long fibers.  Panel on right shows grainy material with no trace of fibers Alzheimer's fibers without DAPH in left panel. Alzheimer's proteins with DAPH in right panel; the fibers have broken up with DAPHDr. James Shorter, University of Pennsylvania School of Medicine

Alzheimer's disease is marked by clumps of protein fibers called amyloids that accumulate around nerve cells in the brain. There are currently no effective treatments, but researchers have recently identified several small molecules that can break up amyloids in the laboratory. A new study reveals how these small molecules affect amyloids, providing insight into potential future treatments for this devastating disease.

The dense amyloid “plaques” in the brains of people with Alzheimer’s and other related diseases are formed by proteins that are normally found in the body but that, for unknown reasons, have misfolded to form amyloids. The misfolded proteins clump together around nerve cells, affecting thinking and decision-making. Scientists still aren't sure that these plaques cause disease, but most agree that they are toxic to brain cells and contribute to symptoms.

Since plaques contain misfolded versions of proteins normally found in the body, any potential treatments must be highly specific to prevent unwanted side effects. Previous research had uncovered a small molecule called DAPH-1 that disrupted amyloid-beta—the type of amyloid found in Alzheimer’s patients. A team led by Dr. Susan Lindquist at the Massachusetts Institute of Technology and Dr. James Shorter, who is now at the University of Pennsylvania, set out to investigate how DAPH-1 works. To do this, they took advantage of the well-studied yeast protein Sup35, which converts to amyloid in a manner similar to DAPH-1. The effort was supported by NIH’s National Institute of General Medical Sciences (NIGMS) and others.

The researchers reported in the Proceedings of the National Academy of Sciences on May 14, 2008, that DAPH-1 was able to dissolve amyloids, as well as prevent new fibers from growing from preexisting amyloids. They tested several related molecules as well and found that 2 of them, DAPH-7 and DAPH-12, were also effective at disrupting amyloids and preventing them from forming.

The molecules worked on both amyloid-beta and the yeast Sup35 protein, even though these amyloids have completely different protein sequences. They were ineffective, however, against the other amyloids the researchers tested them against. These results demonstrate that drugs could potentially be designed to target specific amyloids.

The researchers used Sup35 to futher investigate how the small molecules affect amyloids and discovered that they target the areas that hold the amyloid fibers together and convert them to a form that is unable to grow. Normally, fibers grow from their ends, but the molecules stopped this growth.

“Presumably DAPH fits very neatly into the crevices between fiber subunits,” Shorter explained. “The small molecule directly remodels fiber architecture.”

This research will now inform the design of more effective agents in the future. Any potential new medication, of course, will need to be tested in live animal models to begin to assess its effects in the body.

—by Vanessa McMains

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