Up-regulation of casein kinase 1ε is involved in tau pathogenesis in Alzheimer’s disease

Hyperphosphorylation of tau and imbalanced expression of 3R-tau and 4R-tau as a result of dysregulation of tau exon 10 splicing are believed to be pivotal to the pathogenesis of tau pathology, but the molecular mechanism leading to the pathologic tau formation in Alzheimer’s disease (AD) brain is not fully understood. In the present study, we found that casein kinase 1e (CK1e) was increased significantly in AD brains. Overexpression of CK1e in cultured cells led to increased tau phosphorylation at many sites. Moreover, we found that CK1e suppressed tau exon 10 inclusion. Levels of CK1e were positively correlated to tau phosphorylation, 3R-tau expression and tau pathology, and negatively correlated to 4R-tau in AD brains. Overexpression of CK1e in the mouse hippocampus increased tau phosphorylation and impaired spontaneous alternation behavior. These data suggest that CK1e is involved in the regulation of tau phosphorylation, the alternative splicing of tau exon 10, and cognitive performance. Up-regulation of CK1e might contribute to tau pathology by hyperphosphorylating tau and by dysregulating the alternative splicing of tau exon 10 in AD.