As many as 5.8 million Americans are currently living with Alzheimer’s disease, a neurodegenerative condition associated with progressive cognitive decline, including loss of memory capabilities . Protein aggregates, composed of beta-amyloid or other proteins, form in the brains of individuals with Alzheimer’s. These beta-amyloid plaques
“We uncovered an important immune cell communication axis that is protective in an Alzheimer’s disease model.” said co-first author Jordy Saravia, Ph.D.
Microglia are immune cells in the brain responsible for clearing beta-amyloid plaques. As Alzheimer’s disease progresses, microglia can lose their capacity to remove these plaques and instead produce inflammatory mediators that may accelerate beta-amyloid plaque progression. The St. Jude team found that accumulating another subtype of immune cells, called CD8+ T cells, is essential to slow this process by interacting with microglia. This interaction, in turn, was important to limit beta-amyloid burden and preserve memory capabilities in a mouse model of the disease.
Previous research has established complex roles for T cells and other immune system cells in Alzheimer’s disease. In particular, research groups using other experimental systems have suggested that certain T cells with inflammatory functions worsen the disease. However, the St. Jude scientists showed that CD8+ T cells with suppressive features accumulate in the brains of both mouse models and patients with Alzheimer’s disease, highlighting that T cells play a complex role 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,” said corresponding author Hongbo Chi, Ph.D. “Our results demonstrate the need to better understand these complex neuro-immune interactions to improve outcomes for this neurodegenerative disease.”
To understand how T cells were delaying symptom progression in their Alzheimer’s disease model, the St. Jude group searched for the most abundant molecular interaction between CD8+ T cells and the microglia. They found a protein on the surface of CD8+ T cells, CXCR6, interacts with the protein CXCL16 expressed by microglia.
“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,” said co-first author Wei Su, Ph.D., St. Jude Department of Immunology. “Moving forward, we may be able to extend this work to find an effective intervention for neurodegenerative diseases.”
Wei Su, Jordy Saravia, Isabel Risch, Sherri Rankin, Cliff Guy, Nicole M. Chapman, Hao Shi, Yu Sun, Anil KC, Wei Li, Hongling Huang, Seon Ah Lim, Haoran Hu, Yan Wang, Danting Liu, Yun Jiao, Ping-Chung Chen, Hadeer Soliman, Koon-Kiu Yan, Jonathan Zhang, Peter Vogel, Xueyan Liu, Geidy E. Serrano, Thomas G. Beach, Jiyang Yu, Junmin Peng, Hongbo Chi. CXCR6 orchestrates brain CD8+ T cell residency and limits mouse Alzheimer’s disease pathology. Nature Immunology, 2023; DOI: 10.1038/s41590-023-01604-z
St. Jude Children’s Research Hospital. “Specialized T cells in the brain slow progression of Alzheimer’s disease.” ScienceDaily. ScienceDaily, 7 September 2023. <www.sciencedaily.com/releases/2023/09/230907130430.htm>.
Photo by National Cancer Institute