Age-related myelin damage leads to white matter inflammation, but its impact on chronic neurodegenerative diseases remains unclear. A recent study reveals that amyloidosis alone can cause age-related oligodendrocyte and myelin damage in mouse models of Alzheimer’s disease. The research team discovered that CD8 T cells contribute to neurodegenerative diseases associated with amyloidosis by abnormally activating microglia, resulting in myelin damage.
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.
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Shreeya Kedia, Hao Ji, Ruoqing Feng, Peter Androvic, Lena Spieth, Lu Liu, Jonas Franz, Hanna Zdiarstek, Katrin Perez Anderson, Cem Kaboglu, Qian Liu, Nicola Mattugini, Fatma Cherif, Danilo Prtvar, Ludovico Cantuti-Castelvetri, Arthur Liesz, Martina Schifferer, Christine Stadelmann, Sabina Tahirovic, Ozgun Gokce & Mikael Simons, 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
Mikael Simons is the project leader of projects A06 and B01, as well as service project Z02.
