Elevation of Casein kinase 1ε is associated with TDP‐43 and tau pathologies in Alzheimer's disease

Alzheimer's disease (AD) is characterized by the presence of extracellular amyloid beta plaques and intraneuronal neurofibrillary tangles of hyperphosphorylated microtubule-associated protein tau in the brain. Aggregation of transactive response DNA-binding protein of 43 kDa (TDP-43) in the neuronal cytoplasm is another feature of AD. However, how TDP-43 is associated with AD pathogenesis is unknown. Here, we found that casein kinase 1epsilon (CK1epsilon) phosphorylated TDP-43 at Ser403/404 and Ser409/410. In AD brains, the level of CK1epsilon was dramatically increased and positively correlated with the phosphorylation of TDP-43 at Ser403/404 and Ser409/410. Overexpression of CK1epsilon promoted its cytoplasmic aggregation and suppressed TDP-43-promoted tau mRNA instability and tau exon 10 inclusion, leading to an increase of tau and 3R-tau expressions. Levels of CK1epsilon and TDP-43 phosphorylation were positively correlated with the levels of total tau and 3R-tau in human brains. Furthermore, we observed, in pilot immunohistochemical studies, that the severe tau pathology was accompanied by robust TDP-43 pathology and a high level of CK1epsilon. Taken together, our findings suggest that the elevation of CK1epsilon in AD brain may phosphorylate TDP-43, promote its cytoplasmic aggregation and suppress its function in tau mRNA processing, leading to acceleration/exacerbation of tau pathology. Thus, the elevation of CK1epsilon may link TDP-43 to tau pathogenesis in AD brain.