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

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Abstract
Alzheimer9s disease (AD) is associated with accumulation of the neurotoxic peptide amyloid-β (Aβ), which is produced by sequential cleavage of amyloid precursor protein (APP) by the aspartyl protease β-secretase and the presenilin-dependent protease γ-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, β-secretase, and γ-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 CK1ε, one of the CK1 isoforms expressed in brain, leads to an increase in Aβ peptide production. Conversely, three structurally dissimilar CK1-specific inhibitors significantly reduced endogenous Aβ peptide production. By using mammalian cells expressing the β C-terminal fragment of APP, it was possible to demonstrate that CK1 inhibitors act at the level of γ-secretase cleavage. Importantly, Notch cleavage was not affected. Our results indicate that CK1 represents a therapeutic target for prevention of Aβ formation in AD.