Alzheimer’s disease, a neurological disorder characterized by gradual cognitive decline, including memory loss, affects up to 5.8 million Americans today. Protein aggregates made up of beta-amyloid or other proteins occur in the brains of Alzheimer’s patients. These beta-amyloid plaques appear to be a major cause of the disease.
Scientists at St. Jude Children’s Research Hospital discovered a subpopulation of immune cells that appear to inhibit the creation of beta-amyloid plaques, as well as the critical proteins involved in the process. Nature Immunology published the findings on September 7th, 2023.
People typically think of the immune system as being involved in defense from bacterial or viral infection, though there is growing interest in the role of the immune system in neurodegenerative diseases. We uncovered an important immune cell communication axis that is protective in an Alzheimer’s disease model.”
Jordy Saravia, Study Co-First Author, Department of Immunology, St. Jude Children’s Research Hospital
Microglia are immune cells in the brain that are responsible for the removal of beta-amyloid plaques. Microglia could lose their ability to clear these plaques as Alzheimer’s disease advances, instead producing inflammatory mediators that may increase beta-amyloid plaque formation.
The St. Jude researchers discovered that increasing another type of immune cell called CD8+ T cells is critical for slowing this process by interacting with microglia. In turn, this connection proved critical for limiting beta-amyloid accumulation and preserving cognitive capacities in a mouse model of the disease.
Our paper is the first to demonstrate that a subpopulation of CD8+ T cells can be protective in a mouse model of Alzheimer’s disease. Moving forward, we may be able to extend this work to find an effective intervention for neurodegenerative diseases.”
Wei Su, Ph.D., Study Co-First Author, Department of Immunology, St. Jude Children’s Research Hospital
Immune Cells’ Opposing Roles in Alzheimer’s Disease
Previous research has revealed that T cells and other immune system cells play intricate roles in Alzheimer’s disease. Researchers employing various experimental settings, for example, have demonstrated that some T cells with inflammatory activities exacerbate the condition.
However, the St. Jude researchers discovered that CD8+ T cells with suppressive properties increase in the brains of both mice models and Alzheimer’s disease patients, indicating that T cells play a complex function in this disease.
We showed that CD8+ T cells can play a protective role against Alzheimer’s disease pathogenesis, although there is also evidence for a contributing role. Our results demonstrate the need to better understand these complex neuro-immune interactions to improve outcomes for this neurodegenerative disease.”
Hongbo Chi, Ph.D., Study Corresponding Author and Member, St. Jude Children’s Research Hospital
The St. Jude team looked for the most prevalent molecular connection between CD8+ T cells and microglia to understand how T cells delayed symptom development in their Alzheimer’s disease model. They discovered that CXCR6, a protein on the surface of CD8+ T cells, interacts with CXCL16, a protein produced by microglia.
A Molecular Handshake Slows Alzheimer’s Disease
CXCR6 and CXCL16, two surface proteins, effectively conducted a handshake between the two cells, communicating in both ways. The contact of these two proteins on the exterior of their respective cells can send information in the same way as the firmness of a human handshake can.
Chi added, “We found CD8+ T cells use CXCR6 to interact with CXCL16 from microglia. Moreover, CD8+ T-cell accumulation, localization and function in the brain are regulated by CXCR6.”
The researchers discovered how the handshake happens and how it prevents the emergence of Alzheimer’s disease-related diseases. The CD8+ T cells go first to the microglia, which are found around the beta-amyloid plaques. The CD8+ T cells then utilize the handshake to notify the microglia to cease producing excessive inflammation, slowing plaque formation and symptoms in mouse models.
Scientists found that mice with the gene for the CD8+ T cell protein CXCR6 removed had worsened signs of Alzheimer's disease. A portion of this impact was caused by the CD8+ T cells lacking CXCR6 failing to gather in the area of the brain near the microglia or plaque location.
Additionally, these cells failed to develop the proper suppressive ability. As a result, the CD8+ T cell’s capacity to shake hands effectively inhibited its protective impact against the signs and symptoms of Alzheimer’s disease.
“We have two major findings. One is the crucial role of CD8+ T cells in maintaining homeostasis of the brain, thereby providing a protective role in Alzheimer’s disease,” Chi further stated.
Homeostasis is the process of maintaining a system’s stability. In this situation, CD8+ T lymphocytes try to reduce the damage produced by microglia malfunction and Alzheimer’s disease-related plaques.
Chi concluded, “The other major finding is identifying the central importance of the T cell protein CXCR6 for CD8+ T-cell accumulation and function in the brain. We really need to characterize these kinds of neuro-immune interactions better. Only by understanding this basic biology can we advance the field and find new treatments.”
Su, W., et al. (2023). CXCR6 orchestrates brain CD8+ T cell residency and limits mouse Alzheimer’s disease pathology. Nature Immunology. doi.org/10.1038/s41590-023-01604-z