Radleys

UIC Chemists Characterize Alzheimer's Neurotoxin Structure

Date Posted: Wednesday, December 12, 2007

Print Email to a friend

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 similar to the final (fibril) form, which wasn't expected at all."

Ishii said a complete determination of the intermediate structure remains to be done, but he is confident his lab will be able to do that. Once completed, the findings may provide pharmaceutical manufacturers with the information they need to create drugs that will prevent interaction between the toxic molecules and nerve cells.

Ishii said the method can also be applied to structural studies of proteins associate with other neurodegenerative diseases, including Parkinson's, and prion diseases, such as Creutzfeldt-Jakob.

"We're also interested in applying our technique in the nanoscience field to examine the formation process of peptide-based nano-assemblies," he said.

The findings are reported online in Nature Structural & Molecular Biology.

UIC students co-authoring the paper include former doctoral student Sandra Chimon, candidates Medhat Shaibat, Christopher Jones and Buzulagu Aizezi, and former undergraduate Diana Calero.

Funding was provided by the National Institutes of Health, the National Science Foundation, the Dreyfus Foundation and the Alzheimer's Association.

Further Information: http://www.uic.edu



Related news from our archive

Microfluidic Chambers Advance the Science of Growing Neurons
Researchers at the University of Illinois have developed a method for culturing mammalian neurons in chambers not much larger than the neurons themselves.

Researchers use new Approach to Predict Protein Function
The study describes an integrated approach using experimental techniques, computational techniques and X-ray crystallography for predicting the function of a protein.

Scientists Identify Gene Involved in Stem Cell Self-Renewal in Planaria
The work could lead to a better understanding of the fundamental mechanisms by which stem cells are regulated.

Compound Reveals Link Between Signaling Protein And Cell Migration
The protein, known as RKIP, controls activity of kinases, a type of enzyme that acts as a key component in the biochemical signaling pathways responsible for determining almost all cellular activity.