Regulation of Alzheimer's disease amyloid-β formation by casein kinase I

Alzheimer's disease (AD) is associated with accumulation of the neurotoxic peptide amyloid-beta (A beta), which is produced by sequential cleavage of amyloid precursor protein (APP) by the aspartyl protease beta-secretase and the presenilin-dependent protease gamma-secretase. An increase of casein kinase 1 (CK1) expression has been described in the human AD brain. We show, by using in silico analysis, that APP, beta-secretase, and gamma-secretase subunits contain, in their intracellular regions, multiple CK1 consensus phosphorylation sites, many of which are conserved among human, rat, and mouse species. Overexpression of constitutively active CK1 epsilon, one of the CK1 isoforms expressed in brain, leads to an increase in A beta peptide production. Conversely, three structurally dissimilar CK1-specific inhibitors significantly reduced endogenous A beta peptide production. By using mammalian cells expressing the beta C-terminal fragment of APP, it was possible to demonstrate that CK1 inhibitors act at the level of gamma-secretase cleavage. Importantly, Notch cleavage was not affected. Our results indicate that CK1 represents a therapeutic target for prevention of A beta formation in AD.