Fingolimod treatment exacerbates tau phosphorylation and neurodegeneration in a mouse model of tauopathy with accumulated brain CD8+ T cells

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Abstract It is known that T cells play an important role in the progression of neurodegenerative disorders, including tauopathies. In this study, we used fingolimod (FTY720), an approved medication for the treatment of multiple sclerosis (MS), to manipulate T cell dynamics in P301S-Tau transgenic (Tau Tg) mice. FTY720 dramatically decreased the population of circulating T cells in blood. However, unexpectedly, we observed a marked increase in the number of CD8+ T cells in the hippocampus of FTY720-treated Tau Tg mice. This increase in CD8+ T cell number was significantly correlated with enhanced tau phosphorylation. Notably, FTY720-treated Tau Tg mice exhibited brain atrophy and neurodegeneration compared with controls. These findings indicate that CD8+ T cells in the brain contribute to the progression of tauopathies, and that brain CD8+ T cells may be a promising target for the treatment of tauopathies. This study provides new insights into the dynamics of brain T cells in neurodegenerative disorders. In addition, these results raise caution regarding FTY720 treatment in individuals predisposed to tauopathies, as it may promote neurodegeneration despite reducing peripheral T cells.

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