New research approach could unlock some mysteries about Alzheimer’s

If successful, approach could have implications beyond the debilitating disease.

A new research project using a unique approach may help unlock clues as to how Alzheimer’s arises and point to potential targets for developing therapeutics to treat the disease.

The project, led by University of Alberta chemists Matthew Macauley and John Klassen, will examine glycans (sugars) that interact with CD33, an important protein that is strongly implicated in Alzheimer’s disease. The primary goal is to develop a strategy for getting more precise information on the molecular identity of these sugars.

Macauley explained that receptors for sugars present in microglia, a specific type of white blood cell found in the brain, can serve as an indicator of who gets Alzheimer’s and who doesn’t.

“There are different forms of this receptor, called protein isoforms, that have been linked to whether people are protected from the disease or not,” said Macauley. “People who are protected from getting Alzheimer’s have a version of that isoform that does not bind to sugars—this is the key.”

“It’s a challenging receptor to study because its glycan ligands have remained somewhat elusive,” said Macauley.

Some sugars bind to isoforms so weakly that they are hard to detect using regular biochemical tests, he explained.

Sophisticated equipment provides unique insights

That’s where Klassen comes in. His research laboratory uses sophisticated mass spectrometers, which will allow the team to detect these glycan-receptor complexes with greater sensitivity and resolution.

Mass spectrometric identification of the interactions is achieved by transferring the complexes from aqueous solution to the gas phase via small, highly charged droplets. Solvent evaporation from the droplets yields gaseous complexes that are charged (ions), which can be weighed by accelerating them in a vacuum and measuring their speed.

“John has a method that is very precise in picking up on very weak binding interactions through this mass spectrometry method,” said Macauley.

Klassen’s approach, called Catch-and-Release Electrospray Ionization Mass Spectrometry (CaR-ESI-MS), is unique worldwide.

“No one else in the world is currently using this approach,” said Macauley. “With John’s high-end mass spectrometer, we will be able to see how the sugars bind to this Alzheimer’s-related protein CD33 at levels that we simply cannot see right now with standard equipment and assays. It’s very exciting.”

Other potential applications

Macauley already sees a therapeutic or diagnostic potential to help or even prevent people from suffering from Alzheimer’s.

“If we can better understand the correlation between sugars and Alzheimer’s, then changing or altering the sugars could potentially alter the disease,” he said, adding he also sees other applications for this approach to his project.

“The immune system is involved in so many diseases, so if this new approach works, there could be a lot of work to do beyond the link of this one receptor to Alzheimer’s,” he said.

“This is exactly the kind of research that we hope will translate into tangible benefits for people worldwide,” said Todd Lowary, scientific director of GlycoNet, which is funding the research project. “Funding research to address health issues and improve quality of life is what is making our organization worldwide leaders in the field of glycomics.”