Abstract
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 1ε (CK1ε) was increased significantly in AD brains. Overexpression of CK1ε in cultured cells led to increased tau phosphorylation at many sites. Moreover, we found that CK1ε suppressed tau exon 10 inclusion. Levels of CK1ε were positively correlated to tau phosphorylation, 3R-tau expression and tau pathology, and negatively correlated to 4R-tau in AD brains. Overexpression of CK1ε in the mouse hippocampus increased tau phosphorylation and impaired spontaneous alternation behavior. These data suggest that CK1ε is involved in the regulation of tau phosphorylation, the alternative splicing of tau exon 10, and cognitive performance. Up-regulation of CK1ε might contribute to tau pathology by hyperphosphorylating tau and by dysregulating the alternative splicing of tau exon 10 in AD.
Highlights
Alzheimer’s disease (AD) is a slow neuroprogressive disorder histopathologically characterized by the presence of senile plaques and neurofibrillary tangles (NFT)
We found that the expression of casein kinase 1ε (CK1ε) was dramatically increased by 2.5 folds in AD brains as compared with controls (Fig. 1A,B)
We found that the level of CK1ε was elevated dramatically in AD brain
Summary
Alzheimer’s disease (AD) is a slow neuroprogressive disorder histopathologically characterized by the presence of senile plaques and neurofibrillary tangles (NFT). NFTs are composed of paired helical filaments (PHF), aggregated polymers of the abnormally hyperphosphorylated tau[1,2]. Tau is the major neuronal microtubule associated protein. In AD brain, tau is abnormally hyperphosphorylated, which leads to loss of its biological activity, gain of a toxic activity, and its aggregation into PHFs7. Adult human brain expresses six isoforms of tau that are products of the alternative splicing of its pre-mRNA from a single gene. Tau exon 10 encodes the second MT-binding repeat, the alternative splicing of which generates tau isoforms with three or four MT-binding repeats, named 3R-taus or 4R-taus, respectively. 3R-taus and 4R-taus differ in their biological function in polymerization and stabilization of neuronal microtubules as well as in their interactions with tau kinases[10,11,12]. Non-cytoskeletal proteins, viral oncogenes, and receptors, CK1 regulates diverse cellular processes, including circadian rhythms, cellular signaling, vesicular trafficking, cell division, and DNA repair pathways[19,20,21,22]
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