Grant: Canada Postdoctoral Research Award (CPRA) program

Alzheimer's disease (AD) is the most common form of dementia, affecting nearly 750,000 Canadians and millions worldwide. A hallmark of AD is the buildup of sticky clumps in the brain called amyloid plaques. Specialized immune cells in the brain, known as microglia, surround and try to contain these plaques, which can help protect nearby neurons. However, not all microglia respond in the same way. Human genetics show that some versions of a microglial receptor called CD33 increase the risk of AD, while others appear protective. We still do not fully understand why these different versions of CD33 have such distinctive effects. This project will study how CD33 shapes the ability of microglia to generate energy and control plaque growth. We will focus on a newly discovered "short" version of CD33, which may fine-tune how microglia handle stress and maintain cellular resilience and balance. Using advanced imaging, powerful genetic models of AD, and next-generation sequencing approaches, we will test whether this short CD33 version helps microglia produce more energy, contain plaques more effectively, and better support surrounding brain cells. By revealing how CD33 influences microglial biology, this research will help explain why certain genetic backgrounds increase or reduce AD risk. Ultimately, it could point toward new strategies to "reprogram" microglia to slow or prevent the progression of Alzheimer's disease.