The three-dimensional structure of the amyloid fibril has been determined by a combination of neutron scattering and NMR studies at Argonne.

Structural details of fibrils, or plaques, aid researchers studying their relationship to Alzheimer's disease.

Research offers clues to Alzheimer’s plaques

With quiet cruelty, Alzheimer’s disease robs the elderly of their most precious possessions: memories. Eventually it takes their lives.

Researchers from Argonne and the University of Chicago have combined nuclear magnetic resonance (NMR), neutron diffraction and chemical techniques to see directly the structure and growth of microscopic filaments that form the characteristic plaques found in the brains of those with Alzheimer’s disease.

No one knows if these “b-amyloid plaques” cause the disease, or are merely a symptom. But as America ages—people over 85 are the fastest-growing segment of the population, and 30 to 40 percent will contract the disease—every clue may help medical science slow or stop the coming epidemic.

This research also has possible applications for nanotechnology, a new field that may bring lighter, stronger materials and faster computers.

Each plaque is a tangle of millions of ribbon-like peptide chains called b-amyloid fibrils. Peptides are organic compounds normally present in the body for physiological processes. Peptides are linked amino acids that form the building blocks of proteins. Inside the body’s cells, amino acids are used for growth, maintenance and repair.

For unknown reasons, certain kinds of peptides begin to “self-assemble” into tangles of fibrils in the brains of persons with Alzheimer’s disease. Researchers know the characteristic amyloid peptides are chains of 43 amino acids. They begin to link, stacking one on top of the other to form ribbon-like structures—the beginnings of a fibril.

But due to the lack of detailed structural information, little progress had been made on understanding fibril structure and self-assembly—crucial to identifying targets for potential drug candidates.

“It was impossible to study the actual assembly process in the whole peptide,” said Pappanan Thiyagarajan, one of the project’s principal investigators. “It’s just too big a molecule to get useful data.”

Cutting the peptide down to size
The researchers literally cut the peptide down to size, truncating the compound by removing amino acids from each end.

“The truncated peptide should still behave like the entire peptide,” Thiyagarajan said. “It will still organize in the same fashion, and since it is less complex than the original, we can easily analyze it with spectroscopy.”

To keep the peptides from combining into larger, more confusing structures, researchers added polyethylene glycol—a water-soluble polymer commonly used as a laxative—to the hydrophobic (water-avoiding) side of each peptide fibril.

“That allowed us to isolate and study individual fibrils, which was instrumental to determining their structure,” Thiyagarajan said.

In addition to electron microscopy performed at the University of Chicago and at Argonne, Nuclear Magnetic Resonance studies were performed by Robert Botto of Argonne’s Chemistry Division.

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