Aperçu du projet

Alzheimer’s disease is the most common cause of dementia and affects hundreds of thousands of Canadians. Both genetic and environmental factors contribute to its development, but recent research highlights the importance of the brain’s immune system—particularly a specialized immune cell type called microglia. Microglia help maintain brain health by removing debris, regulating inflammation, and supporting neurons. When their activity becomes dysregulated, they can instead promote inflammation and contribute to disease progression.

One of the strongest genetic links to Alzheimer’s disease is a gene called CD33, which influences how microglia respond to toxic protein deposits known as amyloid plaques. Depending on an individual’s genetic makeup, CD33 can produce two different forms of the protein. One form (CD33M) increases disease risk by suppressing microglial activity, whereas the other (CD33m) appears to be protective and supports healthier immune responses. Our published work has shown that these two CD33 forms drive these opposing outcomes in Alzheimer’s models—CD33M impairs the microglial response to plaques, while CD33m enhances it—laying the foundation for the present study to uncover the underlying mechanisms. Understanding how these genetic variants alter immune activity is essential for developing therapies that restore healthy microglial function in Alzheimer’s disease.

This project will use advanced molecular and imaging techniques to determine how CD33 isoforms shape microglial behavior. We will examine their effects on cellular localization, metabolism, and communication with other brain cells, using humanized mouse models that express each CD33 variant. By applying cutting-edge spatial and metabolic approaches, we will also map how these mechanisms differ across regions of the brain and in relation to amyloid plaques. Together, these studies will reveal how CD33 genetic variation alters immune function in the brain and identify new biological pathways that could be targeted to prevent or slow Alzheimer’s disease.

Chef d'équipe

Matthew Macauley , University of Alberta  

Membres de l'équipe

Jason Plemel, University of Alberta

Partenaire et Donateurs

Krembil Foundation