This is a summary of Kedia, S., Ji, H., Feng, R. et al. T cell-mediated microglial activation triggers myelin pathology in a mouse model of amyloidosis. publishes in Nature Neuroscience (2024). https://doi.org/10.1038/s41593-024-01682-8

The challenge

Age-related brain damage induces inflammation and poses a significant risk for various neurodegenerative diseases, including Alzheimer’s disease. However, it is unknown how these age-related changes in myelin and oligodendrocytes contribute to the development of these diseases.

Our approach

We used immunohistochemistry and scanning electron microscopy to study oligodendrocyte and myelin changes in a mouse model of Alzheimer’s disease (5xFAD). In 5xFAD mice, we examined increased oligodendrocyte and myelin pathology in both the white and gray matter and detected a small but elevated number of CD8+ T cells. To understand whether CD8+ T cells contribute to oligodendrocyte and myelin responses, we performed antibody mediated CD8+ T cell depletion.

Our findings

Our results show that antibody mediated CD8+ T cell depletion rescued oligodendrocyte and myelin damage in 5xFAD mice. Additionally, CD8+ T cell depletion improved spatial learning and memory. To mechanistically understand how CD8+ T cells drive the pathology, we performed single cell RNA sequencing and identified a decrease in a specific microglia cluster enriched in major histocompatibility complex class II (MHCII) genes in CD8+ T cell depleted mice. We observed an upregulation in MHCII+ microglia populations in the vicinity of T cells in both mouse and human autopsy tissue. We further provide evidence that these abnormally activated microglia display myelin damaging activity.

The implications

Our study provides mechanistic insights into how T cell mediated neuroinflammation can induce oligodendrocyte and myelin pathology. If these results are further validated in human studies, targeting inflammation to specifically improve oligodendrocyte health could offer significant therapeutic promise for delaying AD.

Creating SyNergies

The study, led by SyNergy member Mikael Simons, is a collaboration with SyNergy investigators Arthur Liesz and Martina Schifferer, and LMU, TUM, and DZNE researchers. In future research, we will investigate how tissue-resident CD8 cells, which develop across various neurological diseases, exert their harmful effects and whether these mechanisms are also present in human diseases.