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 were reported online yesterday in Nature Structural & Molecular Biology.
Source: University of Illinois at Chicago
Related stories:
Important Plant Enzymes Identified
Scientists at the U.S. Department of Energy's Brookhaven National Laboratory have identified enzymes important in the modification of isoflavonoids, natural plant products that help plants resist fungal infections, and may have beneficial health effects for humans as well. The research, which will be published online May 22, 2008, in
The Plant Journal, may pave the way for implanting the isoflavonoid-synthesis pathway into bioenergy crops to promote disease resistance and thereby prevent yield losses, and/or to enhance the production of other useful chemical feedstocks.
Study of staph shows how bacteria evolve resistance
Antibacterial resistance doesn’t happen overnight. But until recently nobody knew exactly how long it took — or how it happened at all. Now, by studying blood taken from a single patient over a period of months, Rockefeller University researchers have been able to trace how a common strain of bacteria adapted its genes to counteract the antibiotics used to try to kill it, until it finally emerged into the kind of fully resistant microbe that is wreaking havoc in hospitals worldwide. Total elapsed time: 90 days.
Researchers create nanocages to enclose drug, pesticide molecules
Tiny chemical cages created by researchers at Rutgers, The State University of New Jersey, show potential for delivering drugs to organs or tissues where they're needed without causing harm elsewhere.
Advance brings low-cost, bright LED lighting closer to reality
Researchers at Purdue University have overcome a major obstacle in reducing the cost of "solid state lighting," a technology that could cut electricity consumption by 10 percent if widely adopted.
Gene produces hormones that lead to obesity
(PhysOrg.com) -- Obesity and common weight gain share a genetic basis. Professor Philippe Froguel, from Imperial College in Great Britain, and his team from the laboratoire Génomique et physiologie moléculaire des maladies métaboliques (CNRS/ Université Lille 2 / Institut Pasteur de Lille), in collaboration with teams from Inserm and Danish, Swiss and German partners, have discovered a new obesity gene that plays an essential role in the maturation of several key hormones that control food intake.
Improving Quantum Dot Synthesis
Materials researchers at the National Institute of Standards and Technology have developed a simplified, low-cost process for producing high-quality, water-soluble quantum dots for biomedical applications. By using a laboratory microwave reactor to promote the synthesis of the widely used nanomaterials, the recently published NIST process avoids a problematic step in the conventional approach to making quantum dots, resulting in brighter, more stable dots.
New Nanowire-Based Memory Could Beef Up Information Storage
Researchers from the University of Pennsylvania have created a type of nanowire-based information storage device that is capable of storing three bit values rather than the usual two—that is, "0," "1," and "2" instead of just "0" and "1." This ability could lead to a new generation of high-capacity information storage for electronic devices.
Discovery by UC Riverside physicists could enable development of faster computers
Roland Kawakami's lab proposes a simple technique for controlling electron spin and current flow
Physicists at UC Riverside have made an accidental discovery in the lab that has potential to change how information in computers can be transported or stored. Dependent on the "spin" of electrons, a property electrons possess that makes them behave like tiny magnets, the discovery could help in the development of spin-based semiconductor technology such as ultrahigh-speed computers.