One of the most significant areas of discovery in Alzheimer’s disease (AD) research in recent years has been the role of T cells. T cells are immune cells typically found outside the brain, either in other tissues and organs or circulating in the blood. For a long time, the immune systems of the brain and the rest of the body were considered entirely separate, so T cells were largely ignored in studies of AD. Recent studies have shown that not only does the peripheral immune system impact the brain, but that T cells can enter the brain and play a role in AD progression. The most impactful work in this area found that tau pathology is entwined with T cell infiltration and function. However, the role of these infiltrating T cells in the mechanisms linking sleep and AD remains unknown. Here, Dr. McAlpine seeks to define that role. He hypothesizes that T cells migrate to the brain in response to tau pathology and disrupt networks critical to sleep patterns by releasing the signaling protein IL-3.
To test this hypothesis, Dr. McAlpine proposes two aims. In the first, he and his team will seek to establish the role of T cells and IL-3 in sleep disruptions caused by tau pathology. In tau mouse models, they will either deplete all T cells, knock out IL-3, or prevent T cells from producing IL-3. They will also transfer T cells from tau mice, with or without IL-3, into control mice to determine whether T cells producing IL-3 are sufficient to induce sleep disruptions. In each of these experiments, they will identify changes in sleep patterns. In the context of IL-3, the first aim will focus on its production, and the second on its binding to its receptors. Receptors for IL-3 are particularly abundant on subtypes of neurons found in brain regions critical for sleep. Dr. McAlpine’s team will delete the receptor from those neurons in tau mice and measure if sleep patterns are preserved as pathology progresses. They will also compare the profiles of neurotransmitters in these modified neurons with those in unmodified neurons to capture the full breadth of changes this deletion may cause. By looking at both ends of IL-3’s proposed life cycle in this process, Dr. McAlpine opens the door for multiple therapeutic approaches targeting IL-3 in future work.
Overall, this project will define the role of T cells in sleep disruption associated with tau tangle accumulation and specifically investigate the role of IL-3, which may represent a therapeutic target for preserving healthy sleep in AD.
