Minah Suh of the Department of Biomedical Engineering at Sungkyunkwan University, in collaboration with the biotechnology company IMNEWRUN and Ho-Keun Kwon’s team at Yonsei University College of Medicine, has identified a mechanism by which modulating an immune protein in the brain can restore a disrupted brain immune environment and reduce abnormally elevated neuronal activity in an animal model of Alzheimer’s disease.
The findings provide scientific evidence supporting brain immune modulation as a potential therapeutic strategy for Alzheimer’s disease, a major neurodegenerative disorder. The study was published in the journal Science Advances.
Alzheimer’s disease is characterised not only by the accumulation of harmful protein deposits in the brain but also by dysfunction of cells that help maintain and protect the brain environment. Microglia, the brain’s resident immune cells, rapidly respond to tissue damage and help maintain the surrounding environment. In Alzheimer’s disease, however, normal microglial responsiveness is impaired, while neurons can exhibit abnormally increased activity.
The research team focused on the immune-regulatory proteins PD-1 and PD-L1, which have been widely studied in the field of cancer immunotherapy. In Alzheimer’s disease model mice, the researchers found increased PD-1 expression in microglia and increased PD-L1 expression in astrocytes, which play an important role in maintaining the brain environment. The team then investigated how these changes in immune-regulatory signalling affect brain function.
To address this, the researchers administered an antibody that blocks PD-L1 activity into the brains of Alzheimer’s disease model mice and observed the responses using advanced microscopy techniques that enable visualisation of living brain cells.
The results showed the impaired response of microglia to sites of tissue damage was restored following PD-L1 blockade, while the abnormally elevated activity of neurons was reduced. The researchers also found these effects were more pronounced when PD-L1 was directly modulated within the brain than when the antibody was administered systemically.
Minah Suh said: “This study reveals that disruption of immune-regulatory signalling in the Alzheimer’s disease brain is closely associated with both impaired microglial function and abnormal neuronal activity. Our findings suggest that precisely modulating immune proteins within the brain could provide a new therapeutic strategy for Alzheimer’s disease.”
Taeyoung Park, an integrated M.S.–Ph.D. student at Sungkyunkwan University, served as the first author of the study, while Minah Suh and Ho-Keun Kwon served as corresponding authors.