UIC chemists characterize Alzheimer's neurotoxin structure

Associate professor of Chemistry Yoshitaka Ishii and his team have isolated an intermediate structure of the fiber-like amyloid plaques (fibrils) which, they believe, can be responsible for the nerve cell damage associated with Alzheimer's. Although there is much research required to discover the causes and treatments for this disease, Ishii and his research team of chemists have put forward a new approach to the treatment, and perhaps even the prevention of Alzheimer's.

The degenerative disease known as Alzheimer's is said to be caused by a build-up of proteins in the brain. Amyloid plaques - fiber-like proteins - contribute to this build-up, leading to nerve cell death. The destruction of these nerve cells contributes to the trademark memory loss and other neurological malfunctions that are associated with Alzheimer's.

According to the Alzheimer's Association, amyloid plaques are an overabundance of protein deposits, and in the case of Alzheimer's, it is a buildup of misfolded amyloid proteins. Proteins take up different configurations, sheet-folding being one of them. However, the accumulation of misfolded amyloid proteins somehow contributes to nerve cell degeneration.

"It is not completely understood how the amyloid proteins are formed," said Ishii. "Somehow the small protein called amyloid is overly produced in the brain, and then they form the fibril structure which is extended and pointed in shape."

The final amyloid fibril was then compared to the intermediate structure, which the team discovered has a rich molecular structure in a spherical shape in its early stages, averaging around 20 nanometers in diameter.

Ishii explained that "the spheres eventually assemble into the final fibril amyloid structure." This transitional form of the protein has been found to be more toxic than the mature fibril itself. The final fibrils composed of amyloid-beta proteins trigger nerve cell damage and death, yet the intermediate spherical structures that Ishii and his team have isolated are 10 times more toxic to nerve cells. The team confirmed this by comparing the toxicity of the final amyloid protein to that of the intermediary's.

Ishii has also said that this transitional, intermediate formation is highly unstable, making it extremely difficult to isolate and study. Ishii's approach to separate this intermediate structure of the fibril was to examine its shape with solid-state nuclear magnetic resonance (NMR) and electron microscopes. NMR is a very useful tool in obtaining detailed images of a structure's topography and overall shape in solid state or even in solutions.

"Once the [amyloid protein] assembly grew, we were able to see the visible intermediate structure," explained Ishii.

Electron microscopes utilize electrons to clarify and zoom in on a very small specimen. Ishii's team freeze-trapped the intermediate structure and "studied the amyloid morphology using the electron microscope to see its changes and decide when to freeze-trap. After 30-50 hours, the [intermediate] spheres form, and then the fibril forms, and then the structure elongates."

By pinpointing and isolating this unstable transitional composition of toxic spheres, the team would be able to study how its components and eventual formation trigger nerve cell destruction. Ishii plans to study the complete morphology of both the intermediate and final amyloid structures "to help us identify what makes it so toxic." They are the first team to identify the sheet-forming intermediate structure as the culprit for the protein misfolding that consequently leads to nerve damage.

Ishii is confident that his team of researchers will be able to completely configure the newly-discovered intermediate structure. With further study, the team hopes to understand how this intermediary may contribute to the protein misfolding and build-up.