The study investigates the role of T cell-mediated microglial activation in age-related myelin pathology using a mouse model of amyloidosis. Key findings include: 1. **Amyloidosis and Myelin Damage**: Amyloidosis triggers age-related oligodendrocyte and myelin damage, as evidenced by increased STAT1 CCI+ and Serpina3n CCI+ oligodendrocytes, abnormal myelin ultrastructure, and fragmented premyelinating oligodendrocytes. 2. **CD8+ T Cell Involvement**: CD8+ T cells are elevated in the white and gray matter of 5xFAD mice and contribute to oligodendrocyte and myelin pathology. Depletion of CD8+ T cells reduces myelin damage and improves learning deficits. 3. **Microglial Activation**: Microglia activation, driven by T cells, leads to myelin damage. Treatment with IFNγ increases MHC-II expression and microglial activation, while baricitinib, a JAK inhibitor, reduces this activation and myelin damage. 4. **Behavioral Impairment**: Baricitinib treatment improves learning deficits in 5xFAD mice without affecting anxiety-related behaviors. These findings suggest that immune responses against myelinating oligodendrocytes may contribute to neurodegenerative diseases with amyloidosis, highlighting the potential therapeutic target of inflammation for delaying AD.The study investigates the role of T cell-mediated microglial activation in age-related myelin pathology using a mouse model of amyloidosis. Key findings include: 1. **Amyloidosis and Myelin Damage**: Amyloidosis triggers age-related oligodendrocyte and myelin damage, as evidenced by increased STAT1 CCI+ and Serpina3n CCI+ oligodendrocytes, abnormal myelin ultrastructure, and fragmented premyelinating oligodendrocytes. 2. **CD8+ T Cell Involvement**: CD8+ T cells are elevated in the white and gray matter of 5xFAD mice and contribute to oligodendrocyte and myelin pathology. Depletion of CD8+ T cells reduces myelin damage and improves learning deficits. 3. **Microglial Activation**: Microglia activation, driven by T cells, leads to myelin damage. Treatment with IFNγ increases MHC-II expression and microglial activation, while baricitinib, a JAK inhibitor, reduces this activation and myelin damage. 4. **Behavioral Impairment**: Baricitinib treatment improves learning deficits in 5xFAD mice without affecting anxiety-related behaviors. These findings suggest that immune responses against myelinating oligodendrocytes may contribute to neurodegenerative diseases with amyloidosis, highlighting the potential therapeutic target of inflammation for delaying AD.