Chemists Tap Alzheimer's Protein for Clues

Research involves use of 'atomic force microscope' to produce images of proteins

By Cassie Ferguson

Gazette Staff

Scientists have named a twisted protein that attacks brain cells as a prime suspect in Alzheimer's disease, a degenerative brain disorder that affects 4 million Americans. However, while the scientists can name the likely culprit, they have little idea of how the protein turns into a killer, so Harvard researchers are taking a very close look at its growth for clues.

Peter Lansbury, associate professor of neurology at Brigham and Women's Hospital, uses a powerful microscope to peer at the protein called amyloid-beta as it assembles. He found that the protein first forms tiny seeds which grow into the long, thick strands that make up the core of the waxy plaques found in the brains of Alzheimer's victims.

If doctors could detect the protein seeds, they might be able to stop the production of the toxic form of the protein, possibly preventing the disease.

"The disease progresses for decades, then at some point the person becomes symptomatic. The whole key to Alzheimer's is pre-symptomatic detection," said Lansbury. Currently, there is no definitive diagnostic test for Alzheimer's, the only absolute confirmation of the disease being an autopsy.

"Clearly there's going to be a treatment for Alzheimer's in 10 years," he said. "We are working on a way to be able to directly measure the disease so people can start treating it before it happens."

Learning how to catch the seeds of Alzheimer's before they sprout may have implications for other neurological diseases as well. In the December 1997 issue of the journal Neuron, Lansbury suggested the same mechanism might also play a role in Parkinson's disease, Huntington's, and prion diseases like Creutzfeldt-Jakob, which are all characterized by abnormal protein deposits in the brain.

Tapping the Suspect

An organic chemist by training who works with the biologists and physicians at Brigham and Women's Center for Neurologic Diseases, Lansbury brings an unusual perspective to the study of Alzheimer's. He is among the first to focus a microscope that is primarily used in the field of materials on biological problems.

Lansbury uses an "atomic force microscope" to produce three-dimensional pictures of the individual Alzheimer's seed proteins. The microscope reveals the proteins' topography at a near-molecular resolution.

"It's a powerful technique and it will become more powerful," said James Harper, a postdoctoral researcher in Lansbury's lab.

The microscope works by gently tapping a fine needle across the protein's surface. A laser monitors the needle's movement as it bounces off the protein and a computer translates the information from the laser into a three-dimensional map.

An even more detailed image would require an even finer needle that could stroke the tiniest of crevices on the protein's surface, a delicate challenge being tackled across the river in Chemistry Professor Charles Lieber's lab.

Chemistry graduate student Stanislaus Wong has started building those tips using bunches of nanotubes, carbon tubes several atoms in circumference.

In the January Journal of the American Chemical Society, Wong and his colleagues on both sides of the river reported the first successful use of the nanotube tips in probing the structure of biological specimens, in this case amyloid-beta aggregates.

More recently, Wong and his colleagues in the Lieber lab demonstrated in a paper in the July 2 issue of Nature that the nanotube tips might someday be used to test the chemical nature of individual parts of proteins, creating chemical as well as topographical maps.

Growing Seeds of Destruction

Lansbury and his colleagues grow the amyloid-beta protein in test tubes. Using the microscope to look at the protein during different stages of its growth, they found that it develops from smaller protein seeds.

The protein growth starts out with the small filaments called protofibrils assembling slowly. When the protofibrils reach a critical concentration, longer proteins called fibrils suddenly appear, twisting and sometimes branching as they grow.

"When we looked at the growth over time, we saw that when the fibrils start their explosive growth, the protofibrils disappear," said Harper. The large fibrils sweep up the smaller protofibrils as they grow, proving that the longer amyloid-beta proteins consist of ordered bunches of the shorter protofibrils.

Another feature of the protein that intrigues Lansbury was found by Bradley Hyman, associate professor of neurology at Massachusetts General Hospital, who investigated the detailed structure of amyloid plaques which suggests that the amyloid protein is dynamic, constantly growing and dissasembling.

This raises the tantalizing question, yet to be answered, of whether the process could be reversed, causing the amyloid-beta to disintegrate before it can cause trouble.

"The problem of Alzheimer's forces new ideas," said Lansbury. "I'm interested not only in defining the chemistry of the protein but also in, 'Why would you make proteins liable to do this?' "