UIC chemists characterize Alzheimer's neurotoxin...( Amyloid plaques the hallmark of Alzh...),Health

Amyloid plaques, the hallmark of Alzheimer's disease, are clumps of fiber-like misfolded proteins which many experts think cause this devastating neurodegenerative disease.

While effective treatment remains an elusive goal, new research by University of Illinois at Chicago chemists suggests a possible new approach.

Yoshitaka Ishii, associate professor of chemistry, and his students managed to capture and characterize a crucial intermediate step in the formation of amyloid plaque fibers, or fibrils, showing tiny spheres averaging 20 nanometers in diameter assembling into sheet-like structures comparable to that seen in formation of fibrils.

Fibrils made of small proteins called amyloid-beta are toxic to nerve cells, but intermediate spheres, including those identified by Ishii's group, are more than 10 times as poisonous. That has made the spherical intermediates a new suspect for causing Alzheimer's disease.

"The problem with studying the structure of this intermediate form is that it's so unstable," said Ishii. His team's approach, he said, was to 'freeze-trap' the fleeting intermediate form, then use solid-state nuclear magnetic resonance to determine its structure and electron microscopes to study its morphology, or shape.

Ishii and his coworkers confirmed that the intermediate spherical stage of amyloid is more toxic than the final-form fibrils. Their findings are the first to pinpoint sheet formation at the toxic intermediate stage in the misfolding of the Alzheimer's amyloid protein and support the notion that the process of forming the layered sheet structure might be what triggers toxicity and kills nerve cells.

"Our method characterized the detailed molecular structure of this unstable, intermediate species," Ishii said. "To the best of our knowledge, this is the first characterization of detailed molecular structures for toxic amyloid intermediates. We found that the structure was very simila
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