Chemists discover how a plaque-fighting protein protects against Alzheimer’s

Scientists at the University of Alberta have identified a new mechanism for a protein that decreases the chance of developing Alzheimer’s disease—a discovery that highlights a new potential avenue for developing therapeutic treatments.

The protein, called CD33, is known for its connection to Alzheimer’s disease susceptibility, but its exact role was unclear until now. 

There are two versions, or isoforms, of the CD33 protein: a long version that increases susceptibility to Alzheimer’s disease and a short version that decreases the chance of getting the debilitating neurodegenerative disease. 

“We found that the short isoform has a completely different and opposite function from the long isoform,” explained Matthew Macauley, assistant professor in the Department of Chemistry and Canada Research Chair in Chemical Glycoimmunology. 

“The short version of the CD33 protein makes immune cells in the brain, called microglia, better able to consume plaque-causing proteins, which contrasts to the long versions of CD33, which we previously showed represses this process.” 

About 10 per cent of the population have a different version of the CD33 protein that causes them to make more of the short isoform of CD33—which means that 90 per cent of people could benefit from a therapeutic intervention, Macauley explained.

“Our ultimate goal is to translate this new information into a therapeutic treatment strategy,” he explained. “There are several different avenues to accomplish this, which we are pursuing with new funding our laboratory has received.” 

The new research builds on Macauley’s previous work studying the CD33 protein

Co-authors on the study include research associate Abhishek Bhattacherjee and PhD student Jaesoo Jung in Macauley’s lab, as well as Jason Plemel, an assistant professor of medicine and neurology in the Faculty of Medicine & Dentistry and member of the Neuroscience and Mental Health Institute.

Funding for the research was provided by the Alzheimer Society of Canada, the Canadian Institutes of Health Research and GlycoNet. Macauley is also an investigator with GlycoNet, a Canada-wide network of researchers based at the U of A who are working to further understanding of biological roles for sugars.

The study, “The CD33 short isoform is a gain-of-function variant that enhances Ab1-42 phagocytosis in microglia,” was published in Molecular Neurodegeneration.

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