Over half a million Canadians are living with dementia, according to the Alzheimer Society of Canada, but the physical, psychological, social, and economic impacts ripple far beyond that number, affecting caregivers, family, and society as a whole. The World Health Organization estimates that Alzheimer’s disease accounts for 60–70 per cent of dementia cases, and a cure is not yet available. While Alzheimer’s disease remains challenging to study due to its slow progression, GlycoNet researchers have been taking exciting steps towards developing a therapeutic treatment.

“One striking observation made in the last 5–10 years is that genetic factors that can influence your susceptibility to Alzheimer’s disease converge on immune cells in the brain, called microglia,” says Matthew Macauley, GlycoNet researcher and Canada Research Chair in Chemical Glycoimmunology at the University of Alberta (U of A).

In Alzheimer’s disease, neurodegenerative plaques begin forming decades before manifestation of the disease, and it’s at this early stage of disease progression that Macauley and his team are studying how microglia influence formation of these plaques.

“Not only do the quality of microglia—defined by a person’s genetic make-up—influence the tendency to develop plaques, but it also influences how the microglia respond to the plaques once they are developed,” explains Macauley. “In the brain, as the plaques start to develop, the microglia try their best to contain them in different ways. But in the process of trying to do so, they can change and develop into versions that are better or worse in fighting the disease.”

Macauley emphasizes how his team is fortunate to be able to collaborate with other investigators that have significant expertise in microglia. This has enabled the Macauley lab to begin unravelling how a carbohydrate-binding receptor, called CD33, controls microglia and Alzheimer’s disease susceptibility. One of these key collaborators is GlycoNet researcher and assistant professor Jason Plemel at the U of A. Last year, the research team discovered that a short version (isoform) of CD33, found in only about 10 per cent of people, decreases the chances of developing Alzheimer’s disease. They determined decreased susceptibility may be due to improved function of the microglia. At the earlier stages of the disease, microglia can eat, or “phagocytose,” smaller fibres called fibrils that eventually go on to form plaques, suggesting that the protective variant of CD33 lessens disease susceptibility through making microglia more proficient in this ability.

Finding the right carbohydrate to unlock immune cell function

Studying how the short version of CD33 functions motivated Macauley and his team to investigate what the long version of CD33 is doing and, in particular, what carbohydrates it recognizes.

“The short version can’t bind to carbohydrates, but the long version can,” says Macauley. “That’s a really important point, because it implies that maybe the carbohydrates themselves in the brain are related to the etiology of Alzheimer’s disease.”

Since joining U of A, the Macauley Lab has collaborated closely with GlycoNet researcher and U of A professor John Klassen to address the question of what carbohydrates bind to the long version of CD33.

“Recently, we made a big breakthrough, which is that CD33 can bind to carbohydrates that have a chemical modification called sulfation,” says Macauley. “We are very excited by these findings because carbohydrate sulfation is important in the brain.”

Sulfation is essentially a “decoration” to the carbohydrate, like an ornament on a Christmas tree. “Those decorations can make a really big impact for recognition by CD33,” explains Macauley.

The research team’s findings related to carbohydrate sulfation were recently published in ACS Chemical Biology.

Developing a potential therapeutic strategy

Using their knowledge of CD33 as a carbohydrate-binding receptor and its ability to control microglia, Macauley and his team have been developing a strategy to target the long version of CD33. They synthesized a carbohydrate that binds specifically to CD33, and attached it on onto liposomes—nanoparticles with a lipid bilayer that mimics cell membranes. These liposomes are safe, FDA-approved, and often used as drug delivery vehicles.

“The liposomes engage CD33 on microglia and cause CD33 to be transported inside the cell,” explains Macauley. “This is a process called endocytosis and it’s a natural process, so we are in a way just exploiting its natural function. Driving CD33 inside the cell means that it is no longer where it needs to be to control microglia and, hence, it changes the function of the microglia.”

U of A assistant professor Anastassia Voronova has been a key collaborator on this research involving liposomes. The team’s findings were recently published in the Journal of Controlled Release last fall.

Next steps

“Our initial proof-of-concept study provides the motivation for using this approach to make the microglia better at stopping the accumulation of plaques and, hence, slowing down Alzheimer’s disease,” says Macauley. “These studies are at early stages and our team is excited about their potential.”

The research is funded by GlycoNet, the Alzheimer Society of Canada, Weston Family Foundation, and the Canadian Institutes of Health Research.

January is Alzheimer’s Awareness Month in Canada, bringing awareness to the disease and supports available.