Duke chemists isolating individual molecules of toxic protein in Alzheimer's, Parkinson's disease

March 16, 2005

SAN DIEGO -- To understand the formation of the brain-clogging deposits that cause such disorders as Alzheimer's and Parkinson's diseases, Duke University chemists have figured out how to capture and "micromanipulate" the single molecular building blocks of the deposits.

Their aim is to understand the detailed assembly process for the toxic protein called amyloid plaque. Such basic understanding, they said, could lead to approaches to preventing plaque formation.

The researchers led by Boris Akhremitchev are using the infinitesimal tip of a customized atomic force microscope (AFM) to capture, isolate and study single molecules, called monomers, that are the building blocks of the toxic protein polymers known as amyloid fibrils. Atomic force microscopes use a sharp microscopic tip to image surfaces and detect energy differences by mechanically probing molecular surfaces.

In a poster presentation at the American Chemical Society's annual meeting, the researchers will describe the first biophysical analysis of interactions between monomers that form the amyloid fibrils associated with Parkinson's disease.

This presentation will include studies by Chad Ray, a graduate student in Akhremitchev's research group, that clarify the nature of binding forces between amyloid molecules. The poster session will take place March 16, 2005, 7:30 - 10 p.m. Pacific Standard Time, in Hall D of the San Diego Convention Center.

This work was funded by the Camille and Henry Dreyfus Foundation and by Duke University.

It has been difficult to study the chemistry of formation of these fibrils within the brains of humans and other animals, said Akhremitchev, who is an assistant professor of chemistry.

In the brain, "monomers of all kinds are suspended in a soup in equilibrium," he said. Given that the components of amyloid fibrils measure only billionths of a meter and are floating in a disordered mix, "the initial stages of amyloid aggregation are not fully understood," he said.

"When you start a normal reaction, molecules are free in solution so they interact with each other randomly," Akhremitchev said. "If you want to dissect the process, you would rather want to study interactions individually."

Thus, the Duke chemists capture individual monomers at the end of long chained polyethylene glycol molecules. They then attach one such tethered monomer to a microscope slide and the other to the AFM microscope tip. They can then bring the isolated and suspended molecules together to study how and whether they interact.

The Duke researchers study these interactions by retracting the tip of their AFM, which can measure changes in force at the atomic scale. Pulling back the tip can induce a measurable tug on the chemical bonds that hold together the two elevated monomers.

By pulling on such bonds, the Duke scientists can deduce how much energy was required to bring the molecules together. Then, using their knowledge of protein chemistry, they can develop hypotheses about how those particular monomers might, or might not, be involved in the evolution of fibrils, They can thus develop a better understanding of amyloid aggregation.

The scientists are also seeking the precise point during fibril formation when interactions between monomers become irreversible. Defining that point is important because "the fibrils are virtually indestructible once formed," he said.

"How all these monomers interact to form these amyloid fibrils is just not known at this point," said Akhremitchev. "And that is why it is such a great challenge. That's what we want to learn."

Duke University

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